Research Guide

The main research interests of our laboratory are focused on two areas of investigation:

1) Environmental Cardiology: We are dissecting the mechanisms by which exposure to air particulate matter promotes atherosclerosis and ischemic heart disease and studying gene-environment interactions of relevance in the development of cardiovascular disease. We have determined that air pollutant chemicals such as those present in diesel exhaust particles are able to induce inflammatory genes in endothelial cells, in a synergistic fashion with oxidized phospholipids. This synergy was also present in tissues harvested from animals exposed to concentrated ambient ultrafine particles which are the smallest (<0.18 µm) and most abundant particulate pollutants in urban settings, responsible for the largest promotion of atherosclerosis as compared with particles of bigger size. One of the mechanisms how air pollution appears to promote atherosclerosis is via the generation of dysfunctional HDL that either loses its anti-inflammatory capacity or even becomes proinflammatory.

2) Biology of vascular oxidative stress: We are interested in genes and pathways of relevance in the vascular oxidative stress generated in atherosclerosis and cardiac allograft rejection response, such as heme oxygenase-1 (HO-1) and its transcription factor Nrf2. We have shown that HO-1 is an important antioxidant and anti-inflammatory protective gene that may play a central role in orchestrating the antioxidant defense of vascular cells. We are currently studying how is that HO-1 expression modulates various inflammatory pathways via the use of genetic and biochemical approaches. We have established a good complementation in between our two areas of investigation as it appears that the generation of reactive oxygen species in the vasculature and the expression of Nrf2-regulated antioxidant genes represent important elements in the systemic effects of air particulate pollutants.

My research deals with the events mediating chronic inflammatory processes such as occur in atherosclerosis, cancer and rheumatoid arthritis. Our research employs cell, molecular and biochemical methods to address several questions related to the regulation of the specific interaction of endothelial cells with monocytes.We have identified specific oxidized phospholipids that accumulate in lesions and activate monocyte endothelial interactions. We will use in vitro and in vivo studies to test the role of these lipids, their receptors and signal transduction pathways

Research:  My laboratory is studying the molecular and cellular mechanisms of artery wall calcification, its relationship to osteogenesis and the potential for reversal by osteolysis.

My clinical research interest are:

Predictors of sudden cardiac death

Mechanisms of atrial fibrillation

Cardiovascular disease in women

Our lab studies fundamental mechanisms of contractile failure during cardiac ischemia and failure. In order to do this, we use a single cell model where metabolic inhibitors are applied to mimic these clinical conditions, so that we can investigate ion channel behavior and subcellular calcium movements using the patch clamp technique and ultra-rapid live calcium imaging using laser scanning confocal microscopy. Using this approach, we have been able to calculate the number of ion channels required to generate force production in cardiac tissue. We also use myocytes from animals whose calcium transport proteins have been genetically modified. An fascinating consequence is that modifications of calcium transportproteins,such as the sodium-calcium exchanger, results in compensatory changes in the behavior of potassium and chloride channels. In collaboration with other faculty in the Departments of Medicine, Anesthesia, Physiology, and Molecular Biology, we have studied subcellular calcium handling in other models of heart failure including live imaging of genetically modifed zebrafish

I am looking at clinical outcomes of patients who undergo percutaneous coronary intervention with drug-eluting stents.  In particular, I am analyzing the data in cardiac transplant patients, patients who undergo PCI with left main disease, and diabetic patients.

Research Statement -Aldons J. Lusis

The focus of my laboratory is the identification and analysis of genes and pathways contributing to common forms of cardiovascular and metabolic diseases.

Our early work, in the 1980s, was directed at the development of the mouse as a model for atherosclerosis research, and at the cloning and mapping of genes contributing to lipid metabolism and inflammation. In the early 1990s, we turned to the mapping of complex traits and were among the first groups to perform genome scans for metabolic diseases and atherosclerosis in mouse models and in human pedigrees.
Of particular interest for our lab during the past several years has been the integration of genetics and expression array profiling to better understand the biological circuits involved in metabolic and other complex traits. Just as genetic loci contributing to traits such as adiposity and atherosclerotic lesion size can be mapped in crosses between different strains of mice using quantitative trait locus (QTL) analysis, loci controlling transcript abundance can also be mapped. Correlations between the abundance of different transcripts, and between transcripts and traits, can be used to model biologic networks. Since all genetic variations in a genetic cross are due to DNA differences between the parental mouse strains, the interactions of genes in a network can be assigned direction, and causal interactions can be modeled. Our recent studies suggest that this approach can be used to predict "key driver" genes in traits such as adiposity and atherosclerosis. Studies by others suggest that aspects of this strategy can also be applied to human genetic studies.

The main interest in my lab is understanding the molecular mechanisms that regulate cardiac growth, both proliferative and hypertrophic.  We extensively use genetic murine models in an attempt to correlate molecular insights with whole organ physiology. The long-term goal of my research is to determine the consequences of the cardiac myocyte cell cycle exit in diseases such as congestive heart failure and understand how hypertrophic growth can lead to left ventricular failure. Ultimately, we hope to identify molecular targets that would allow targeted therapy to regenerate myocardium. Occasionally we are involved in testing new clinical therapies for heart failure patients.

Patients with normal or better than normal lipids levels who still develop coronary atherosclerosis.  We study the composition and function of HDL and LDL from these patients. It appears that in these patients that have normal levels of plasma lipoproteins, the turn over of LDL and HDL and their interaction with cells is defective.

We also work on oral apoA-I mimetic peptides that have powerful anti atherosclerotic and anti inflammatory properties

Research Interests:

Lipid mediators of Inflammation, Oxidized lipids, and Atherosclerosis.

My laboratory is interested in understanding the expression and regulation of enzymes involved in lipid metabolism, especially, cyclooxygenases, lipoxygenases and phospholipases and their role in the development of cardiovascular diseases such as atherosclerosis. Together with members of the Atherosclerosis Research Unit my laboratory is also studying the role of oxidized phospholipds in atherosclerosis as well as HDL-associated enzymes that participate in the inactivation of oxidized phospholipids.

I have 2 major projects: gene mutation in cardiomyopathy and gene therapy in cardiac allograft rejection.

Our research involves investigating the mechanism and regulation of atherogenic agents on bio-mineralization.  Specifically, we are interested in the role of oxidized phospholipids and inflammatory cytokines in vascular calcification as well as osteoporosis.  We previously found that these atherogenic agents promote osteoblastic differentiation of artery wall cells while paradoxically inhibiting the differentiation of skeletal bone cells.  These findings suggest that the atherogenic agents may, in part, contribute not only to vascular calcification but also to osteoporosis.  Currently, we are elucidating their effects on skeletal anabolic agents, including parathyroid hormone and bone morphogenetic protein, using both in vitro cell culture and in vivo murine models.
 

• Huang MS, Morony S, Lu J, Zhang Z, Bezouglaia O, Tseng W, Tetradis S, Demer LL, Tintut Y.  Atherogenic phospholipids attenuate osteogenic signaling by BMP-2 and PTH in osteoblasts.  J Biol Chem. 2007 May 22; [Epub ahead of print]
• Jaffe IZ, Tintut Y, Newfell BG, Demer LL, Mendelsohn ME.  Mineralocorticoid receptor activation promotes vascular cell calcification.  Arterioscler Thromb Vasc Biol. 2007; 27:799-805.
• Tintut Y, Demer L.  Role of osteoprotegerin and its ligands and competing receptors in atherosclerotic calcification.  J Investig Med. 2006;54:395-401. Review.
• Demer LL, Tintut Y.  Pitting phosphate transport inhibitors against vascular calcification.
  Circ Res. 2006;98:857-9.
• Abedin M, Lim J, Tang TB, Park D, Demer LL, Tintut Y.  N-3 fatty acids inhibit vascular calcification via the p38-mitogen-activated protein kinase and peroxisome proliferator-activated receptor-gamma pathways.  Circ Res. 2006;98:727-9.
• Demer LL, Tintut Y.  Return to ectopia: stem cells in the artery wall.  Arterioscler Thromb Vasc Biol. 2005;25:1307-8.
• Tintut Y, Abedin M, Cho J, Choe A, Lim J, Demer LL.  Regulation of RANKL-induced osteoclastic differentiation by vascular cells.  J Mol Cell Cardiol. 2005;39:389-93.
• Radcliff K, Tang TB, Lim J, Zhang Z, Abedin M, Demer LL, Tintut Y.  Insulin-like growth factor-I regulates proliferation and osteoblastic differentiation of calcifying vascular cells via extracellular signal-regulated protein kinase and phosphatidylinositol 3-kinase pathways.
  Circ Res. 2005;96:398-400.
• Abedin M, Tintut Y, Demer LL.  Mesenchymal stem cells and the artery wall. Circ Res. 2004;95:671-6. Review.
• Abedin M, Tintut Y, Demer LL. Vascular calcification: mechanisms and clinical ramifications.  Arterioscler Thromb Vasc Biol. 2004;24:1161-70.
• Tintut Y, Morony S, Demer LL.  Hyperlipidemia promotes osteoclastic potential of bone marrow cells ex vivo. Arterioscler Thromb Vasc Biol. 2004;24:e6-10.

The areas of study in which we are currently involved include:

1. Percutaneous closure of patent foramen ovale (PFO) and atrial septal defects (ASD) is performed in our cardiac catheterization laboratory. We are working with the neurology department to understand the association of migraine headaches and PFO's. The students will be involved in obtaining clinical information from our patients who have had PFO's closed.

The students will be involved in the continuation of these clinical studies. They will call the patients that we have treated and administer the Midas questionnaire. We will be assessing whether those patients who report improvement in migraine headaches after closure of the patent foramen ovale maintain relief of their headaches for an extended period of time. In addition, we will be assessing whether there is a correlation between nickel sensitivity to the nitinol device used to close the PFO, and any complications following insertion of the device.

2. We will extend these observations about patent foramen ovale and other conditions that may be connected to it. These include the use of hormone replace the therapy in women who have had a stroke, peripheral thrombosis in patients who have hypercoagulable states, the presence of scintillating scotomata in people who do not have a history of migraine, and patients with early dementia. Patients will be tested for the presence of right to left shunt by performing transcranial Doppler studies. If these studies show a higher incidence of right to left shunt in these clinical conditions, future studies to test whether the PFO is causally related will be justified.

3. We are reviewing the transesophageal echos in patients who have had cryptogenic stroke. We will correlate the size of the PFO on transesophageal echo with the size of the stroke measured by integrating the tomographic cross-sectional areas from MRI images.

4. We are working to develop newer forms of PFO closure that will require less material to be permanently implanted in the human heart.

5. I am the cardiology principal investigator for a national multicenter randomized trial that will test the hypothesis that PFO closure will significantly reduce the incidence of migraine headaches. This trial, called the PREMIUM study, is sponsored by AGA medical, maker of the Amplatzer device.

Dr. Weiss's current research interests range from the molecular to the integrated level, with a particular emphasis on integrating experimental and mathematical biology. They include:

1. Arrhythmia biology. The mechanism of sudden cardiac death due to ventricular fibrillation is being studied using interdisciplinary experimental and mathematical approaches. The experimental component uses high resolution multielectrode and optical arrhythmia mapping in intact tissue and monolayers, and patch clamp and fluorescent dye studies in isolated cells. The theoretical component integrates nonlinear dynamics (including chaos theory) with computer simulations of spiral and scroll wave reentry in 2D and 3D cardiac tissue. The goal is to use insights from nonlinear dynamics to develop novel gene- and pharmacologic- and pacing-based therapeutic strategies. This work is currently supported by an NIH/NHLBI Program Project.

2. Ischemia biology and cardioprotection. Viewing cardiac metabolism as a network of interlinked pathways (glycolysis, glycogenolysis and mitochondrial) regulated by multiple protein kinase signaling pathways, our goal is to integrate experimental and mathematical approaches to understand global system-wide responses of metabolism to stresses such as ischemia/reperfusion. A major focus is on the role of the mitochondrial permeability transition (MPT) in ischemia/reperfusion injury and ischemic preconditioning, using biochemical and imaging techniques in isolated mitochondria and isolated cardiac myocytes, as well as proteomic approaches in collaboration with the Dr. Peipei Ping's laboratory. Major goals are to understand the mechanism by which mitochondrial ATP-sensitive K channel agonists and protein kinase signaling pathways are cardioprotective, and to investigate mitochondrial depolarization waves triggering MPT in cardiac myocyte and thereby accelerating cell death. Mathematical modeling is geared to identify emergent properties at the system-wide level which act as switches determining cell fate. We are also studying the mechanisms of cellular K and Na imbalance in heart during myocardial ischemia and hypoxia. This work is currently supported by an NIH/NHLBI Program Project.

We focus on understanding the hypertriglyceridemia associated with a deficiency of GPIHPB1, and diseases associated with defects in the nuclear lamina. Our studies rely on the biochemical approaches, molecular and cellular biology, and the development of genetically modified mouse models.

Nutrition Research in cancer prevention and in the prevention and treatment of obesity in humans, in experimental animal, and  in cell culture models with a focus on protein as a satiating macronutrient that maintains muscle mass and function, and on the effects of phytonutrients from colorful fruits and vegetables beyond antioxidation on cell signalling in diabetes, heart disease, and cancer.

Research Interests: My laboratory is interested in the health benefits of flavonoids from green and black tea, vegetables and other natural products. Specifically the research is focused on the bioavailability, metabolism and antioxidant effect of these flavonoids from teas, fruits and vegetables. This includes the assessment of breakdown products and metabolites of tea flavanols and their health benefits. In addition I am interested in a new area of research investigating the effect of these phytochemicals on oxidative DNA damage and repair and the oxidative alteration of proteins using proteomics.

Kurt Hong, M.D., Ph.D., is a Physician Nutrition Specialist at UCLA Center for Human Nutrition. Dr. Hong's clinical interests include nutritional oncology, weight management, and disease-specific nutrition support. Dr. Hong received his M.D. from the Harvard Medical School and his Ph.D. in Molecular and Cellular Pathology from UCLA. Dr. Hong is currently the Director of Lynda and Stewart Resnick ImmunoNutrition Laboratory at UCLA, where he oversees research studying the link between obesity-related inflammation and risk of prostate and colon cancer. Dr. Hong is dual board certified in Internal Medicine and Clinical Nutrition.

Dr. Zhaoping Li’s primary research areas of interest are in nutrition and obesity, and the role of phytochemicals and botanical dietary supplements in the prevention and treatment of common forms of cancer and cardiovascular disease. She has served as the Associate Chief for the Division of Clinical Nutrition and the Director for the Clinical Research Unit. She supervises the clinical research core, which consists of registered dietitians, research coordinators and clinical fellows. Currently there are 5 ongoing projects studying the effects of phytonutrients on oxidative stress, inflammation, cancer, body composition and memory: 3 industry sponsor studies for treatment of DM and obesity.

Dr. Kim's basic science research projects are funded by the National Institutes of Health, the Dermatology Foundation, and the American Society for Dermatologic Surgery. Dr. Kim's laboratory currently focuses on two specific areas:

1. Studying the mechanism of Toll-like receptor responses (innate immunity) in skin diseases.
2. Determining genes that are important in the development and progression of skin cancers.

The primary objective of my research it to understand how the family of Toll-like receptors (TLRs) helps modulate the direct functions of the innate immune system such as phagocytosis, and the indirect functions such as T cell activation. Recently we discovered that activation of human peripheral blood monocytes through TLRs triggers their differentiation into distinct populations of DC-SIGN+CD16+ macrophages and CD1b+ dendritic cells. DC SIGN+CD16+ macrophages are phagocytic, capable of both the binding and uptake of mycobacteria. Therefore, DC-SIGN+ macrophages represent a population of cells capable of carrying out the direct function of the innate immune response. In contrast, CD1b+ dendritic cells express critical T cell co-stimulatory molecules, secrete cytokines such as the Th1 skewing IL-12 and potently trigger T cell activation. Therefore, CD1b+ dendritic cells represent a population of cells capable of carrying out the indirect function of the innate immune system, triggering T cell activation, and bridge the innate and adaptive immune responses. Current studies are aimed at further elucidating the distribution and function of DC-SIGN+ macrophages and CD1b+ dendritic cells in normal and diseased tissue and their role in combating microbial infections.

Dr. Lee is primarily interested in autoimmunity and immune dysregulation. She is NIH funded and her studies involve 3 major areas:

1. Erythema nodosum leprosum as a model of type III immune complex hypersensitivity reactions
2. Leukocyte immunoglobulin-like receptors and their role in immune dysregulation
3. Gene expression profiles of lesional and non-lesional skin in vitiligo

The Lo Lab (Department of Medicine/Dermatology & Jonsson Comprehensive Cancer Center) studies cutaneous melanoma with the following focus:

1. Defining core gene pathways critical for human melanocytic malignant transformation using an integrated genomic approach,
2. Identifying novel molecular therapeutic targets such as glycogen synthase kinase-3 (GSK-3) and dissecting the mechanism(s) of action, and
3. Understanding the genomic mechanisms of sensitivity/resistance to targeted therapeutics using specific GSK-3 and Braf inhibitors as model targeted small molecule inhibitors.

Current laboratory members:
Roger S. Lo, M.D., Ph.D.
Principal Investigator
M.D., Ph.D.- Cornell/Rockefeller/Memorial Sloan-Kettering Cancer Center rlo@mednet.ucla.edu

Ramin Nazarian, Ph.D.
Postdoctoral Fellow
Ph.D.- UCLA
rnazarian@mednet.ucla.edu

Will Xie, Ph.D.
Postdoctoral Fellow
Ph.D.- University of Science and Technology of China wxie@mednet.ucla.edu

Qi Wang, Ph.D.
Postdoctoral Fellow
Ph.D.- UCLA
wangqi@mednet.ucla.edu

Past and present support for our work comes from the Dermatology Foundation, The American Skin Association, the American Society for Dermatologic Surgery, the Los Angeles Metropolitan Dermatology Society, the Ian Copeland Melanoma Fund, the California Institute of Regenerative Medicine, the Burrough’s Wellcome Fund, and the STOP CANCER Foundation.

My research interests involve the study of mechanisms of cutaneous host defense against bacterial skin pathogens. There are an increasing number of studies demonstrating that Toll-like receptors (TLRs) respond to components of bacteria and other microbial pathogens and subsequently initiate innate and adaptive immune responses. Our preliminary data is a mouse model system of Staphylococcus aureus induced skin ulceration suggest that TLRs and TLR signaling molecules are important in cutaneous host defense against bacterial skin infections. The hypothesis of these studies in that TLRs play a crucial role in initiating innate and adaptive immune responses that are important in controlling bacterial skin infections. My research involves the investigations of the role of TLRs and TLR related signaling molecules in an infection and to generate immune responses such as production of antimicrobial peptides, recruitment of immune system cells, and initiation of innate and adaptive immune. In addition, since cultured keratinocytes and epidermal keratinocytes from human skin specimens have been shown to express TLRs, we are investigating the functional role that human keratinocytes have in sensing and initiating cutaneous host defense mechanisms against Staphylococcus aureus in culture. We believe the insights obtained from the study of TLRs in bacterial skin infections will help broaden our understanding of cutaneous host defense and allow for much needed novel antibacterial therapies, which may be of particular importance since there are increasing numbers of bacterial strains that are resistant to conventional antibiotic therapy

Infectious disease poses a major health problem worldwide. Essential to control of these diseases is the elucidation of immune mechanisms which result in resistance versus susceptibility to infection. Our laboratory's focus is the identification of novel mechanisms by which the innate and adaptive immune system combat microbial pathogens. Mammalian Toll-like receptors comprise part of the innate response. Our group studies the microbial ligands that activate Toll-like receptors and the functional consequence of Toll activation.

We are interested in the mechanism by which Toll activation influences the adaptive T cell response, the mechanisms by which Toll activation leads to direct antimicrobial pathways and role of Toll-like receptors in causing tissue injury in disease. The adaptive T cell response recognizes peptide antigens in the context of MHC molecules and lipid antigens presented by CD1 molecules. We are identifying novel peptide and lipid antigens that are immunodominant in the human immune response to infection as well as mechanisms by which these T cells can directly kill the foreign invader. Using the knowledge of these antigen presentation pathways, we are engineering new vaccine strategies against these pathogens. It is hoped that the insights obtained from these studies will lead to better treatments and prevention of infectious diseases in humans.

Dr. Ochoa's research interest is the study of the immunologic mechanism of host response in infectious diseases of the skin, especially as it relates to the pathogenesis of leprosy and HIV. She recently established that the antimicrobial protein granulysin was present in leprosy lesions and found that CD4+ T cell lines derived from leprosy skin lesions were cytolytic and mediated an antimicrobial activity against infected targets. Studies with granulysin continues to draw attention over its possible use as a new drug for the treatment of infectious diseases. These investigations will contribute to the development of new immunomodulatory therapies for a variety of dermatologic diseases.

The overall research objectives in my laboratory are to identify basic mechanisms of innate and adaptive immunity to infection. One major research project concerns identifying mechanisms whereby dendritic cells (innate immune system) activate T cells (adaptive). Dendritic cells express pattern recognition receptors that allow the cells to recognize conserved microbial structures. Recognition of microbial patterns by pattern recognition receptors, in particular Toll-like receptors (TLRs) activates both direct antimicrobial activity and indirectly modulates the adaptive immune response of B and T cells. TLR1 and TLR2 combine to form a pattern recognition molecule for microbial lipoproteins. We found that TLR1 and TLR2 are co-expressed on dendritic cells in lymphoid tissue. The coexpression of TLR1 and TLR2 on dendritic cells provides the host with the ability to respond to a variety of microbial ligands at sites conducive to the generation of an immune response. We have also found that bacterial lipopeptides stimulate T helper 1 responses in an accessory cell-dependent manner in vitro. We are currently investigating the mechanism of adjuvant activity of TLR ligands and identifying the T cell subset that is responsive to TLR ligands.

The second major research topic of the laboratory is to define the role of T cells in response to infection. We have investigated the role of CD1-restricted T cells in mycobacterial disease for the past ten years. CD1 is an antigen presentation pathway similar to major histocompatibility (MHC) antigen presentation, but with a major distinction, that is the presentation of lipid antigens in contrast to the peptide antigens presented by MHC. We have identified glycolipid antigens of mycobacteria that activate CD1-restricted T cells and provided evidence suggesting that CD1-restricted T cells contribute to immune responses that limit mycobacterial infections. Currently we are investigating the precise chemical structures of the glycolipid antigens that activate CD1-restricted T cells. We are also expanding our investigations of CD1-restrict

A third major area of investigation is to determine the mechanism of T cell help for auto-antibody production in systemic lupus erythematosus (SLE). The ability of T cells to provide help to B cells depends on their recognition of appropriately presented antigen on the surface of B cells. We have found that CD4-, CD8- double negative (DN) T cells in SLE patients promote IgG production in a CD1c-restricted manner, whereas DN T cells of healthy donors exhibited weak helper activity. Our data suggest that CD1c-restricted T cells from SLE patients can provide help to CD1c-expressing B cells for IgG production and could therefore promote pathogenic auto-antibody responses in SLE.

Dr. Adams' research interests lie in the general fields of 1] vitamin D and steroid hormone metabolism and action and 1] common diseases of the skeleton like osteoporosis. While vitamin D has long been known to be required for the normal development and maintenance of human bone and muscle, Dr. Adams has been instrumental in the introduction to the research and clinical world to the necessity of vitamin D and its metabolites in the maintenance of the normal human immune response to common infectious agents like Mycobacterium tuberculosis. As it turns out, at the same time our planet is warming, its human inhabitants are exposed less and less to sunlight with a consequent decrease in vitamin D synthesis in the skin . This has caused a world-wide problem of vitamin D insufficiency, especially among women and children in heavily pigmented populations in the developing nations of Africa and Asia. The Adams basic and clinical laboratories are actively engaged in studies to broaden our understanding of the consequences of this broad-ranging problem of vitamin D insufficiency on human health and disease.

The long-term goal of my research is to understand the molecular mechanisms that govern beta cell formation during embryogenesis and the expansion/regeneration of beta cell mass in adult. Strategies for tackling these complex problems include the generation and analysis of null mouse mutants, development of cell-type-specific inducible transgenic mice, as well as approaches to expand beta cells in vitro and develop methods to drive embryonic stem cells to a beta cell fate. As diabetes results from an inadequate mass of functional beta cells the mechanisms that regulate the number of beta cells will be key to understanding both the pathogenesis of diabetes and for developing therapies.

To understand mechanisms that govern beta cell formation during embryogenesis we have focused on deciphering how complex patterning information controlling differentiation and proliferation of pancreatic progenitor is integrated during the process of organogenesis. Work from our laboratory has identified genes involved in this binary decision process of progenitor cells during the development of the pancreas. Several of these genes are cell cycle regulators acting in the G1 phase, including cyclins and cyclin-dependent kinase inhibitors. More recently we have begun to investigate the role of epigenetic changes that regulate pancreatic progenitors self-renewal and their differentiation into beta cells. We have begun a systematic analysis on the role of polycomb genes and DNA methyltransferases involved in mediating epigenetic changes that are essential in driving cells from a progenitor state to functional beta cells as well as the involvement of epigenetic in diabetes. Such studies will provide the basis for cellular therapy for diabetes

This laboratory's research interests are in the mechanisms that lead to beta cell failure in both type 1 and 2 diabetes, and how these might be prevented and/or reversed. There are approximately 2 million people with type 1 diabetes and 30 million with type 2 diabetes in the USA. There are opportunities for both basic and clinical research in the Butler research program. The basic research is carried out in the Larry Hillblom Islet Research Center, a purpose built islet research center designed with training of methods in islet biology as a major priority. To foster training the Larry Hillblom Islet Research Center houses research cores with expert technical help and state of the art equipment. The Center has published 10-20 papers per year since it was opened. Trainees from the center have won numerous awards locally and nationally.

The Butler research program welcomes interested IM residents to visit the laboratory and explore options for both basic and clinical research projects.

As part of the Hillblom Islet Research Center, Dr. Georgia works to understand how the number of insulin-producing beta cells affects the development or amelioration of diabetes. Her focus is on how insulin-producing beta cells emerge from pancreatic progenitor cells. Her work has made contributions to understanding how replication is involved in the establishment, expansion, and maintenance of beta cell mass in mouse models, both healthy and diabetic. Currently, her interest is on how epigenetic regulation of cell fate genes specifies the identity of beta cells during differentiation.

Dr. Heaney's laboratory research focuses on pituitary and neuroendocrine tumors with an aim to identify novel tumor targets, and characterize candidate potential anti-tumor ligands. Neuroendocrine tumors originate in highly differentiated cell types, express clear phenotypic markers and are excellent models in which to study cellular transformation, providing unique insights into early transforming events in cancer. Current projects examine in vitro and in vivo effects of dietary sugars in cancer development, and progression. Utilizing metabolomic approaches with C13-labelled sugars, we are examining carbohydrate (CHO) metabolism in cancer cells to better understand effects of refined CHO consumption on in vivo cancer growth. In a parallel project, unique phosphorescent nanoparticles are being targeted using highly specific peptide ligands to image and treat neuroendocrine tumors. Our ultimate goal is to translate these technologies to patients with neuroendocrine tumors.

Dr Hevener's laboratory is focused on elucidating the tissue specific functions of nuclear receptors, e.g. the estrogen receptor and peroxisome proliferator activated receptor (PPAR)g, in the regulation of inflammation and insulin action. The primary goal of this laboratory is to better understand the molecular underpinnings of insulin resistance and the relationship between insulin resistance and chronic disease. Tools used include mouse genetics to generate models of chronic inflammation, insulin resistance, obesity, type 2 diabetes and atherosclerosis. In vivo, in situ and in vitro approaches are used to study disease pathology as well as identify novel molecular targets that can be exploited pharmacologically to bring about insulin sensitization and ameliorate chronic disease

Research in Dr Hewison’s group is focused on steroid hormone function, with specific emphasis on the role of hormone metabolism in determining the effects of vitamin D and glucocorticoids. Major projects include studies characterizing the effects of vitamin D on human immune responses and the clinical consequences of this interaction. Dr Hewison’s group has a particular interest in the cellular/molecular mechanisms by which vitamin D deficiency may predispose to common diseases such as inflammatory bowel disease and other prevalent clinical problems such as preterm birth. Other projects are focused on better understanding of how cells acquire and metabolize vitamin D, as well as novel mechanisms which influence nuclear signaling by vitamin D. Dr Hewison’s group is NIH-funded and currently includes four postdoctoral researchers.

In research ethics, we hope to do studies of a multimedia consent form to enhance subject understanding of complex experiments. The student should have programming and artistic capabilities.

In endocrinology, we have observed a high incidence of non-PTH hypercalcemia in liver transplant candidates and recipients. This is unreported and we need to try to understand the derangement that is taking place here.

We know that there are distinct changes in the serum lipids associated with androgen administration to hypogonadal men. It would be valuable to study the before and after state of oxidized serum lipids in relation to androgen therapy.

More than 100 million people worldwide have Type 2 diabetes (TTDM) or its precursor impaired fasting glucose. TTDM compromises quality of life by causing serious microvascular and macrovascular complications (blindness, renal failure, heart attack, stroke) and premature death. Primary metabolic abnormalities in diabetes include impaired insulin secretion and insulin resistance. The pancreatic islet in people with TTDM is characterized by ~ 65% deficit in insulin secreting "beta" cells. Recent studies from our laboratory reveal that this decreased number of beta cells leads to an abnormal pattern of insulin secretion which in of itself may contribute to insulin resistance in type 2 diabetes. This link between the pattern of how insulin is secreted and the impact of this pattern on how well it works is the primary focus of active investigation. Our research goals are 1) to establish the underlying mechanisms of diminished pulsatile insulin secretion in Type 2 Diabetes and 2) to ascertain the consequence of impaired pulsatile insulin secretion on hepatic insulin action. To accomplish this our lab uses an integrative approach ranging from the molecular level to a number of in-vivo animal models. Specifically, we seek to investigate how does the pattern of insulin delivery affects the molecular basis of insulin signal transduction pathways in the liver and how does it control expression of genes regulating hepatic glucose release.

This laboratory's research interest is in mechanisms of diabetes, metabolic syndrome and cardiovascular complications. The major goal is to unravel contributions of nuclear hormone receptors (PPARs, LXRs), adiponectin/adiponectin receptors, chemokine/receptors (MCP-1/CCR2) and metabolic/vascular risk factors in diabetes, obesity and atherosclerosis. Using an integrated multidisciplinary approach of molecular, cellular, biochemical, pharmacological and gene-chip microarrays, specific hypotheses are being addressed both in vitro (human and mouse cell models) and in vivo models. Approaches to address specific regulatory mechanisms of nuclear receptors in diabetes and cardiovascular disease include gene transfer/bone marrow transplantation, pharmacological/dietary intervention in transgenic and tissue specific-gene targeted models. These studies seek to systematically define mechanisms critical to the control of diabetes, metabolic syndrome and atherosclerotic cardiovascular disease. The ultimate goal is to identify novel molecular targets for therapeutic intervention.

The research interests of Dr Michael Yeh include inflammatory pathway biomarkers as diagnostic and prognostic indicators in thyroid neoplasms (collaboration with Jianyu Rao, MD, Dept of Pathology). We are currently building an endocrine tissue bank. We plan to analyze these samples with RNA microarray and proteomic techniques to look for alterations in inflammatory gene expression. Inflammatory processes lie at the intersection of tumor initiation and tumor progression in thyroid neoplasms. Our long-term goals are to develop inflammatory biomarkers for clinical decision making as well as to gain insight into basic mechanisms of malignant progression.

Effects of pancreatic resection on insulin secretion and glucose homeostasis (collaboration with Peter Butler, MD, Division of Endocrinology, and Drs. Reber and Hines from our Division). This research effort is the first of its kind - the goal is to characterize short and long term perturbations in glucose regulation in patients who have undergone pancreatic resection. Physiologic studies will be performed on human subjects and correlated with measures of beta cell viability. We hope to use our findings to develop a clinical model for glucose intolerance and to answer basic questions RE the role of the beta cell in development of type 2 diabetes.

Web-based applications to enable multicenter research collaboration. We are more than 70% complete in programming our on-line endocrine database, which will launch in early 2007. Further efforts are needed to refine the system and expand its scope to support multicenter trials. Trainees with programming experience are encouraged to join our project.

My major research interest is concerned with understanding the functional organization of the mammalian retina by elucidating its morphology and neurochemistry.  Specific investigations are focused on defining the microcircuitry of the outer and inner retina, evaluating the neurochemical organization and regulation of both its fast (amino acid) and slow (peptide) transmitter systems, and the function of bipolar, amacrine and ganglion cell populations, which are major retinal cell types that play critical roles in the processing of visual information. A major emphasis is on morphological, neurochemical and physiological studies concerned with the modulatory action of neurotransmitters and neuropeptides on visual information processing. These investigations provide fundamental knowledge about the functional organization of the retina and form the basis for understanding normal retinal function and the pathophysiology of retinal dysfunction.

Clinical research: Hepatocellular carcinoma and Cholangiocarcinoma.

Methods Employed: Cell Immobilization techniques & Tissue/Cell Culture, Biomaterials testing & implantation, biophysics

PI: Vivek Dixit, Ph.D.

Research Focus: Cell (Hepatocyte or other) Transplantation & related technology

Methods Employed: Animal models for liver disease/failure, Cell physiology, Tissue/Cell Culture

My clinical research studies focus on novel diagnostic imaging and remote data acquisition technologies for the digestive disease tract. These diagnostic and therapeutic devices include push enteroscopy, intra-operative endoscopy, and capsule endoscopy. We have extensive experience with conducting prospective, multi-center, randomized controlled trials for gastrointestinal bleeding disorders such as gastroesophageal variceal hemorrhage, peptic ulcer disease, angiomas, as well as GI tumors. In addition, we conduct pre-clinical studies at the VA Animal Research Facility to evaluate new diagnostic and therapeutic devices in animal models. We also collaborate with other GI Division members with expertise in clinical epidemiology, natural history, and outcomes studies of gastrointestinal bleeding. Some areas of our ongoing research include endoscopic treatments for hemorrhoids, prophylactic therapy non-bleeding esophageal varices, bleeding peptic ulcer, angioma, and studies of the role of non-steroidal anti-inflammatory drugs and Helicobacter pylori in peptic ulcer bleeding.

My research field is the neurophysiology of pain and analgesia. The overall goal of my work consists in investigating cellular and molecular mechanisms that mediate central sensitization in the spinal cord. Central sensitization, a process that underlies numerous chronic pain disorders, consists in the long-term increase in the intensity of nociceptive signals that reach the spinal cord and are then sent to the brain, where they become conscious pain sensations. Recent discoveries have revealed that by substance P and its receptor, the neurokinin 1 receptor, play an important role in mediating central sensitization. On the other hand, endogenous opioid peptides are the natural way for the body to reverse central sensitization. I have developed a new methodology consisting in measuring the activation of neuropeptide receptors by their internalization. Most G protein-coupled receptors are internalized after agonist binding, and this internalization can be detected using antibodies against the receptor. Thus, if a given stimulus produces receptor internalization, it can be inferred that it has elicited the release of endogenous agonists that activate that receptor. In my laboratory, we use electrophysiology techniques to deliver precise electrical stimulation to spinal cord slices or to live animals, while performing intracellular and axonal recordings to monitor neuronal activity evoked by the stimulation. We also study animal behavioral responses to pain in order to measure analgesia. This multidisciplinary approach allows us to map the neuronal circuitry and characterize the pharmacological properties of the signalling systems that activate opioid receptors and substance P receptors in the spinal cord.

The research activities of this laboratory are focused on the identification of extracellular factors and intracellular signal transduction pathways that stimulate cells to divide.

Study of the regulation of COX-2 expression by GI neuropeptides and hormones through novel G-protein signaling pathways.  Regulation of signaling of G-protein coupled receptors by endocytosis and intracellular trafficking.

Experimental research is directed to the understanding the neuroanaotomical and neurochemical circuitries and peptides involved in brain-gut interactions with special focus on the regulation of gastric and colonic secretory and motor function, food intake and visceral pain. The role of neuropeptides particularly corticotropin releasing factor signaling system in the central and peripheral regulation of gut function under stress condition is investigated using functional, pharmacological, electrophysiological, neuroanatomical, and molecular approaches. Models of psychological, immunological and viscerosensory stress including water avoidance, colonic distention, endotoxin and abdominal surgery are used to dissect the neuronal pathways and neurotransmitters altering gut function. These studies relate to the underlying mechanisms of postoperative gastric ileus, functional bowel disorders, and regulation of appetite.

My research is focused primarily in brain-gut interactions, particularly as relevant to irritable bowel syndrome. Methodologically we are using autonomic measurement, fMRI, pain sensitivity testing, and psychological measures. Some studies include pharmacotherapy. I also have an interesting complementary and alternative medicine, particularly traditional Chinese Medicine and hypnotherapy.

I conduct studies in health services, focused primarily on dementia recognition and care with an emphasis on quality assessment. I also do interventional research in quality improvement in primary care settings.

Research Interests:

1.Menopause

2.Osteoporosis

3.Mammographic density

My area is epidemiological research of antioxidants and their relations to inflammation, mortality, and functional status in older persons.

Research Interests:

1.Risk assessment/stratification of older adults, for various health outcomes

2.Identification of physiological pathways by which psychosocial stresses are transmitted to physical health

Research Interests:

1.Measurement of quality of care in older persons

2.Effect of quality of care on health outcomes

3.Improving care of older trauma surgery patients

Research Interests:

1.Aging and alcohol

2.Sedatives

3.Opioids

4.Prescription medications

5.Hispanics and alcohol

Research Interests:

1.Health services delivery

2.Measurement of quality of care

3.Practice redesign to improve quality of care

4.Integration of EHR into outpatient practice

5.Measurement of physical functional status

Research Interests:

1.Prevention of functional decline among underserved older adults, including underrepresented minoritites (Latinos) and the oldest old (octogenarians).

2.Role of beliefs about aging on health behaviors, especially physical activity

3.Community-based participatory research methods

4.Exploration of the construct of geriatric frailty

My overall research focus is on the design and evaluation of healthcare information technology. Current projects include studies of Web-based physician education, electronic prescribing systems, disease registry systems, telemedicine for diabetic retinopathy screening, and the use of information technology to address healthcare disparities.

Dr. Brown?s main areas of interest are:

1.  Quality of care for adults with diabetes and other chronic conditions

2.  Racial/ethnic and socioeconomic disparities in health

3.  Neighborhood influences on health

Research Areas: osteoporosis, menopause, menopausal hormone therapy, mammographic breast density, and their interrelation

Dr. Cranston?s areas of interest include anal dysplasia in the context of immunosupression by HIV, HIV/STD co-infection, rectal microbicide development to prevent HIV infection.

Research addresses racial, ethnic and social disparities in health and health care, barriers to medical care, use of services, HIV prevention and health outcomes.  Populations of interest include persons with HIV and diverse older persons.  Dr. Cunningham is Director of the Investigator Development Core for the NIA-funded Resource Centers for Minority Aging Research (RCMAR), Director of the Training Core for the NCMHD-funded project Export, and an Associate Director of the newly refunded Robert Wood Johnson Clinical Scholars Program at UCLA.  He teaches courses on race, ethnicity and health, health services organization and outcomes and effectiveness research.

My interests are in studying disparities in access to and receipt of medical care:
Decreased access to needed health care among medically indigent adults.
Role of a publicly funded system of health care for low-income/uninsured patients.
Access and quality of breast cancer care for low-income women in California
Variation in CRC outcomes by race and ethnicity: stage at presentation and mortality.
Variation in risk factors and prevalence of CVD and diabetes among African Americans
Racial and ethnic groups at elevated risk for diabetes.
Women's health and variation by sexual orientation.

Mental health services; immigrant/refugee mental health; disaster and terrorism preparedness; violence and mental health trauma; community based participatory research; political violence/human rights

Economic incentives in health care, effects of competition, racial and ethnic disparities in care, social determinates of health, technological change in medicine.

Dr. Ettner's research interests focus on how players in the health care system (patients, providers, health plans) respond to economic incentives, as well as study design and methodology.

Research interests are focused on community-based trials to improve preventive care, including cancer screening.  Current venues to reach the older population include congregations and primary care practices, especially small practices where preventive care is often sub-optimal.  A model of communication that has been shown to be effective in improving preventive care is being tested in two trials throughout southern California as is the effectiveness of working through the congregational leaders to improve the health of their membership.

Health-related quality of life outcomes; patient evaluations of health care; health-related behavior

Research Interests:

1.The causes and consequences of hyperkyphosis in older persons

2.Gene-nutrient interactions and age-related diseases, including cognitive decline, cancer, and osteoporosis

3.T cell senescence and osteoporosis

in the category Breast Cancer - Quality of Care studies.
1) Mentoring an intern/resident in writing a clinical vignette
2) Mentoring an intern/resident in research.

Study design, statistical analyses and modeling, particularly for repeated measures longitudinal data and complex survey data. Measurement and prediction of HIV medication adherence, treatment interruption, pathway to drug resistance, and the linkage between medication adherence, drug resistance and RNA viral load. 

 Reserach Interests: My research focuses on improving the care that older Latinos and African Americans with diabetes receive. As part of this research, I am currently a principal investigator for a project funded by the Centers for Disease Control to study the quality of care for persons from ethnic and racial minority groups with diabetes in managed care settings. I am also conducting a randomized community-based empowerment intervention among older Latinos and African Americans with diabetes to improve their self-care skills. I also have a long-standing interest in the relationship between visual disability, falls and functional decline among the elderly.

Research areas: Patient Satisfaction
Latino and Immigrant Health
Cross-Cultural Health Survey Research Methods
Item Response Theory
Health-Related Quality of Life
Web page: http://www.bol.ucla.edu/~sergio/

Dr. Ong?s research interests lie in applications of health economics to issues in general internal medicine, particularly the economics of tobacco control and improving depression diagnosis and treatment in primary care settings.  I also am interested in improving health services delivery by academic medical centers.

Dr. Shapiro?s areas of interest include disparities of care, quality of care, and HIV.

Dr. Tisnado's research interests include the study of how characteristics of the structure of care and community-level factors affect access and quality, especially for care of complex health conditions such as cancer, and how these issues impact racial/ethnic disparities in access to and quality of health care.

My areas of research are:  Clinical ethics, End-of-life decisions, Quality of Medical Care and Physician-Patient Communication.

Research Area: My main research area is examining patterns of disease and mortality and their contribution to existing racial/ethnic and socioeconomic disparities in life expectancy.  This work will help understand where disparities are greatest and help direct future research and policy targeting the elimination of health disparities.

Dr. Zingmond examines clinical care and outcomes in three topic areas: the elderly receiving long term care, HIV/AIDS, and hospitalized persons receiving surgery.

Title: Investigate stability of RNA interference in human lymphocytesThe Specific Aims are:To further characterize the effects of shRNAs upon primary human T-lymphocyte populations and to understand the mechanisms underlying the cytotoxic effects of shRNA.To test the hypothesis that modulation of shRNA expression levels, in different cellular compartments, and/or different processing pathways is responsible for shRNA mediated cytotoxicity. To extend the in vitro results of Aim 1 and 2 to in vivo animal model systems and to assess the effects of shRNAs during differentiation from hematopoietic progenitor cells to mature T-lymphoid cells.

In the broader context of understanding host defense, my laboratory is interested in defining mechanisms underlying the function of immune cells.  To address these mechanisms we are defining the impact of external and internal factors that compromise immune function.  These include drugs of abuse, specifically cocaine and marijuana, and infectious agents such as human immunodeficiency virus (HIV).

I perform first-in-human clinical trials of new anti-cancer drugs, called phase I clinical trials. Phase I trials are performed in patients with advanced malignancies that are refractory to other treatment options. The purpose of a phase I trial is to determine the side effects, recommended dose, pharmacokinetic behavior, biomarker response, and preliminary data about the anti-cancer activity of a new drug. I have concentrated my efforts in drugs targeting molecules involved in signal transduction. My current and recently completed studies include drugs targeting histone deacetylase, heat shock protein 90, insulin-like growth factor, checkpoint kinase 1, protein kinase C, HER2, pan-ERB, and VEGFR.

The overall research interests of this laboratory are to understand, at the molecular and cellular levels, how the human retroviruses, human immunodeficiency virus (HIV) and human T-cell leukemia virus (HTLV), cause AIDS and cancer, respectively. We are also developing gene therapy reagents and modeling these reagents utilizing the SCID-hu mouse, which allows stem cell reconstitution and thymic T-cell development.

Dr. Steve Cole's laboratory studies neuroendocrine regulation of human, viral, and tumor genomes. The lab combines genome-wide computational analyses with molecular studies of transcriptional regulation to define the signaling pathways by which social and environmental factors influence antiviral responses, inflammation, angiogenesis, tumor invasion, and metastasis.

My research activities at UCLA include translational studies that either originated in the laboratory and led to clinical trials or originated from clinical lymphoma samples that were instrumental in identifying potential new therapeutic targets. The laboratory focuses on: Functional validation of candidate/target genes associated with lymphoma progression, Novel targeted therapies aiming at Ebstein Barr Virus (EBV) positive lymphomas, Cytotoxic lentiviral vector targeting of CD30-positive Hodgkin's lymphoma (HL) cells. In addition, I conduct investigator and industry sponsored clinical lymphoma trials, which include the combination of proteasome inhibitors and Rituximab, novel anti-CD20 antibodies in follicular lymphoma and anti-CD40 antibodies in aggressive Diffuse large B-cell lymphomas.

The focus of my research is on the identification of novel targets for screening and therapy in ovarian cancer. I am studying genes that are amplified and overexpressed in ovarian cancer by Fluorescent In Situ Hybridization, immunohistochemistry to tumor tissue microarrays, and Northern Blot and microarray analysis of gene expression. I have also developed frozen tumor tissue microarray technology and created over 25 tumor microarrays to support research projects of different tumor subtypes used for analysis of DNA, RNA, and proteins.

My research program is focused on the study of determinants of Human Immunodeficiency Virus that may be important for HIV vaccine development. These include structure/function studies of viral proteins, as well as analysis of antibody responses induced by native and modified viral proteins. My laboratory focuses its effort on the in vitro and in vivo testing of novel HIV vaccine candidates. The overall goal of my program isto better understand determinants of HIV that are important for inducing protective humoral immune responses which could be incorporated into successful HIV vaccine regimens.

I split my time between patient care and laboratory research. My research interests are focused around identifying predictive markers for response to novel therapeutics across different solid tumor types. We use lab models of these cancers to understand which patients are more likely to benefit from new therapies that "target" specific genes in cancer cells. The idea is to use the models to then help guide successful clinical trials.

I have a large research program that is focusing on the late effects of cancer treatment in cancer survivors as well as cancer prevention in those at high risk for cancer. Studies ongoing in my lab are examining the role of physical activity and stress management in reducing the risk of breast cancer recurrence in younger women with breast cancer; another study is examining the impact of breast cancer treatments on cognitive function associated with chemotherapy and endocrine therapy; other studies are examining the risks for the development of breast cancer in high risk women through studies of SNPs in double-stranded DNA repair pathways and in the prolactin receptor gene pathways; an additional study will examine the levels of vitamin D and the risk for breast cancer recurrence.

Dr. Garon's research focuses on developing novel therapies for cancers that have traditionally been difficult to treat, namely lung cancer and pancreatic cancer. In his laboratory work, he focuses on determining molecular subtypes of these common cancers. He then evaluates the effects of novel therapeutics against these different subtypes. In addition to laboratory research, Dr. Garon is the primary investigator on several clinical trials. The ultimate goal of his work is to determine subgroups of cancer patients most likely to respond to certain therapies, then translate those observations into rational clinical trials.

My research is in the development of novel therapeutics for cancer, and I have specific interests in the treatment of breast and ovarian cancers, as well as the treatment of melanoma.

My clinical research has involved the development of novel agents in the treatment of gastrointestinal malignancies. This has encompassed writing and leading a large number of studies ranging from single institution phase I trials to large multinational phase II trials and most major gastrointestinal malignancies. This study showed that pegfilgrastim was safe when integrated with every other week chemotherapies and reduced the risk of severe neutropenia.

My research focuses on breast cancer. Basic research project is evaluating the mechanism of action of trastuzumab, and whether or not the immune system plays a role. I also have 8 clinical trials either open or in development evaluating novel therapies for early or late stage breast cancer.

My research interests focus on the development and maintenance of the human T-cell compartment and the pathogenesis of HIV-1. Specifically, I have three complimentary research interests: 1) understanding the impact of aging on the quantity and quality of the human T-cell response to pathogens, 2) investigating the capacity of the thymus to contribute to T-cell reconstitution in HIV-1 infected individuals, and 3) understanding the cellular immune response to vaccination against, or infection with, HIV-1. My overall goals are to identify new areas for therapeutic intervention to either prevent infection with HIV-1, or to delay the progression to AIDS once an individual becomes infected. In addition, I strive to identify therapeutic strategies to increase both the kinetics and extent of T-cell reconstitution in individuals who have suffered a loss of peripheral T-cells.

The overall research interests are to understand, at the molecular and cellular levels, how angiogenesis and signal transduction can be interrupted to achieve an anti-cancer effect. This is studied both in-vitro and in-vivo and the resultant observations form the basis of my clinical trials.
I am the Medical Director of the Thoracic and GU malignancies Program and do clinical investigation in Thoracic and GU malignancies. My clinical trials are TRANSLATIONAL in nature with drugs that target EGFR, Her2, VEGF AXIS etc and include : 

1. Trials in Non-Small Cell Lung cancer
2. Trials in Prostate cancer
3. Trials in Kidney cancer
4. Trials in Bladder cancer.

Residents and fellows spend elective time in the lab or in the clinic with me. 

My general research interest is signal transduction and gene regulation in immunity and cancer. We have been working on a family of nuclear proteins named PIAS (protein inhibitor of activated STAT), which possesses SUMO (small ubiquitin-related modifier) E3 ligase activity. Our studies show that PIAS proteins regulate multiple cytokine signaling pathways, including STAT and NF-kB pathways. Using Pias1 null mice as an animal model, we further demonstrate that PIAS1 is a physiologically important negative regulator of both STAT1 and NF-kB, and that PIAS1 plays an important role in the regulation of inflammation and innate immunity. Our recent studies further demonstrate that the transcriptional regulatory activity of PIAS1 is regulated via Ser90 phosphorylation in response to various signals. Our studies reveal a novel signaling pathway in which pro-inflammatory stimuli activate the IKKa-mediated sumoylation-dependent phosphorylation of PIAS1 for the immediate repression of inflammatory gene activation. Our current research is focused on the role of PIAS1 in adaptive immunity and cancer using combined biochemical and genetic approaches.

The goal of this project is to develop and clinically test a unique direct-acting thrombolytic enzyme, plasmin, that has the potential to prove safe thrombolytic therapy.  Intracranial hemorrhage complicates thrombolytic therapy using plasminogen activators in up to 2% of patients with peripheral arterial occlusion and 10% of patients with ischemic stroke.  Our approach will focus on the biochemical properties of plasmin which provide heretofore unutilized advantages over currently-approved thrombolytic agents, which are indirect-acting plasminogen activators.  Our prior studies show that plasmin delivered locally in vitro or in vivo is as effective as TPA for thrombolysis even more effective when local plasminogen content is limited.  Furthermore, animal studies show that plasmin is safer than TPA, devoid of hemorrhagic consequence even at 4-fold higher doses than needed for thrombolysis.  The proposed studies are designed to translate our fundamental observations to clinical practice.  Specific aim 1) is to evaluate the hemostatic safety of plasmin in animal models of bleeding, using the rabbit ear puncture model to evaluate antiplasmin as a safety monitoring tool and as an antidote for bleeding and a rabbit embolic stroke model to assess the risk for parenchymal (intracranial) hemorrhage.  Specific aim 2) is to translate basic observations to Phase I studies in humans, specifically, for catheter delivery to adult and pediatric patients with thrombosed venous access catheters, for local intravenous treatment of upper extremity deep vein thrombosis, and for intra-arterial treatment of acute ischemic stroke.  The animal studies will be performed at Los Angeles Orthopaedic Hospital/UCLA, and the clinical trials will take place in the Center for Health Sciences/David Geffen School of Medicine at UCLA.  We hypothesize and anticipate that plasmin will provide clinically-effective thrombolysis without an increased risk of bleeding.

Dr. Naeim research is focused on Aging and Cancer. In that regard, his interests are predominately health services oriented examining issues of cost-effectiveness, decision-making, functional decline, comorbidity, quality of life, and survival. He also participates in developing clinical cancer trials specifically aimed at a frail population. He also as a growing interest in the role of informatics in managing, improving care, and measuring outcomes in an older cancer population.

My research focuses on H37/RBM5 lung cancer tumor suppressor gene, located at chromosomal 3p21.3, deletion of which region is the most frequent and the earliest of genetic alterations occurring in lung cancer. For example, loss of heterozygosity (LOH) of 3p21.3 occurs in more than 80 percent of all lung cancer types and even in normal lung epithelia of smokers who have not developed lung cancer yet. Because of this remarkable impact, historically it has been believed that so called "golden" tumor suppressor gene(s) must reside in this region waiting to be developed into a particularly promising cancer therapeutic/diagnostic tool.

Some of these research endeavors include: 1) Generation of conditional H37 gene knock-out mice; 2) Microarray analysis to identify H37-regulated, downstream genes; 3) Yeast two-hybrid screening to identify its protein interacting partners.

1. Basic research into the causes of drug resistance to kinase inhibitor therapy in chronic myeloid leukemia
2. Basic research investigating new drug therapies for chronic myeloid leukemia
3. Basic research studying the molecular pathogenesis of myelodysplastic syndrome
4. Clinical trials of novel drugs for chronic myeloid leukemia
5. Clinical trials of new drugs and drug combinations for aplastic anemia and myelodysplastic syndrome
6. Clinical trials of novel drug therapies for myelofibrosis and polycythemia vera

My research focuses largely on the biology and treatment of women’s cancers, with an aim toward translation of basic research findings to the clinic. Our ongoing research efforts in the laboratory are aimed at the following:

1. Role of HER-2 and EGF receptor signaling in antiestrogen resistance in breast cancer.
2. Extranuclear ER forms in target cells.
3. Targeting ER-a and ER-b  in human non-small cell lung cancers (NSCLC).

Targeting tumor vasculature and growth factor receptor pathways in human cancers.

I am engaged in performing clinical research in the area of treatment options for patients with lymphoma and chronic lymphocytic leukemia. I am particularly interested in treatment options for patients with skin and T-cell lymphomas.

Dr. Ribas is conducting studies aimed at developing new treatment approaches for patients with melanoma. This work spans from laboratory research to patients and includes tumor immunology and targeted therapies. Dr. Ribas and colleagues are working on the pre-clinical and clinical development of CTLA4 blocking monoclonal antibodies, dendritic cell vaccines, genetically engineered antitumor lymphocytes, engineering of immune response to tumors starting from stem cells, and the use of targeted small molecule inhibitors to pharmacologically sensitize cancer cells to immunotherapy.

My research is currently focused on Phase III trials of the oral direct anti-Xa anticoagulant rivaroxaban: (1) prevention of stroke in chronic atrial fibrillation compared to standard therapy; and (2) as a replacement for standard therapy in the treatment of acute deep leg vein thromboembolism.

Our research program area carries out clinical trials with novel agents and devices in support of patients with acute myelogenous leukemia, acute lymphoblastic leukemia, chronic leukemias, and multiple myeloma.  We also have an active component of our program devoted to clinical studies in allogeneic and autologous hematopoietic stem cell transplantation.  Our patient referrals come from a large clinical practice devoted to diseases of the blood and bone marrow.

The overall research interest in Dr. Ke Shuai's laboratory is to study the regulation of cellular signal transduction pathways. These studies may provide novel therapeutic targets for the treatment of cancer and immune diseases.Our work is currently focused on understanding the role of PIAS (protein inhibitor of activated STAT) proteins in cellular signaling. In studies aimed at the understanding of cytokine-activated JAK-STAT signaling pathway, our laboratory has discovered the PIAS family of proteins, which can inhibit the activity of STATs. In addition, PIAS proteins have also been shown to possess SUMO (small ubiquitin-related modifier) E3 ligase activity and can regulate a number of other transcription factors, including p53 and androgen receptor. We are studying the molecular mechanism, the regulation, and the biological roles of PIAS proteins in cellular signaling using a combined biochemical and genetic approach.

I perform translational research on sarcoma and melanoma. This includes testing novel therapeutics on panels of malignant cell lines, evaluating molecular signatures. I have also been working on deterring if stem cells play an active role in these malignancies.

I have interests in the use of transplantation in the treatment of malignant and nonmalignant disorders; and in processes to improve outcomes in transplantation. I also am interested in treatment of hematologic malignancies and hematologic disorders.

My clinical practice is limited to lymphomas and related B cell malignancies. My research focuses on the treatment of lymphomas with active vaccines and monoclonal antibodies. Our work involves preclinical animal models, human tissues, and clinical trials. Our goal is to develop effective immune-based cancer treatments that lack the severe side effects associated with conventional cancer chemotherapies.

My research focuses on characterization of glioblastoma (GBM) stem cells, which are previously unrecognized subpopulation within tumors that are likely responsible for tumor regeneration. We characterize the properties of GBM stem cells in cellular, molecular, functional and genomic levels. We aim to identify key factors and potential pathways that trigger the dysregulated self-renewal and proliferative differentiation, which lead to the sustained tumorigenesis. Findings from these studies will contribute fundamental information towards establishing the identity and possible role of GBM stem cells in tumor recurrence and resistance to treatment. Ultimately, these knowledge and experimental results may translate into new strategies for novel therapy development and drug discovery that can specifically block the GBM stem cell-mediated tumor recurrence.

My current research interests involve performing clinical trials combining chemotherapy with targeted agents in all GI malignancies, including some of the less common ones like esophageal, stomach and gastrointestinal stromal tumors. He also works in an NCI funded laboratory investigating molecular targeting and defining which patients may benefit from different therapies.

My interests are in the pathogenic processes of HIV-1 infection, and in thymopoiesis. My laboratory concentrates on developing model systems which are more relevant to the pathogenic process in man than are standard in vitro culture approaches, with the eventual goal of using these systems to develop therapeutic strategies for AIDS. We are currently concentrating on four major areas of investigation regarding HIV, which include: 1) use of the SCID-hu mouse as an in vivo model for HIV-1-induced pathogenesis and therapeutic approaches. Studies currently ongoing investigate factors involved in viral latency, factors interacting in immune reconstitution following pharmacologic therapy and novel therapeutic approaches including gene therapy; 2) development of novel in vitro culture systems which mimic the in vivo situation; 3) molecular analysis of reverse transcription defects in non-dividing lymphocytes; 4) elucidation of factors involved in age-associated thymic involution. We will continue to develop new model systems and explore existing models to answer important questions regarding the mechanisms associated with HIV disease progression. The members of my laboratory feel that increasing the basic knowledge base regarding HIV pathogenesis will allow a more rational approach to the development of therapeutics to either cure or greatly reduce the morbidity associated with this disease. Lastly, we have more recently begun to explore the hematopoietic differentiation potential of human embryonic stem cells. We feel that these can be harnessed to genetically enhance immune responses to cancer or infectious diseases. In addition, this type of approach can be used to protect the immune system itself from infection, and as a tool to study basic mechanisms involved in hematopoiesis.

My research is focused on the potential roles of periostin (PN) in ovarian cancer progression and metastasis. PN is frequently overexpressed in many human tumors including ovarian cancer and implicated in tumor angiogenesis and metastasis. Our group has prepared a novel function-blocking monoclonal antibody against PN and currently is testing its anti-tumor effects in mouse model.

Debika Bhattacharya MD is currently a Clinical Instructor with the UCLA Infectious Diseases Division. She is an HIV researcher and clinician specializing in HIV and viral hepatitis coinfection. A recent graduate of Stanford University's Infectious Diseases fellowship, her research involves the molecular epidemiology of HIV and hepatitis B coinfection. She conducts HIV and viral hepatitis coinfection clinics at Olive View Medical Center and the West Los Angeles Veteran's Affair Medical Center where she also precepts medical students and residents in the care and management of HIV and viral hepatitis coinfection. Dr. Bhattacharya also has ongoing international collaborations in the field of HIV and hepatitis B coinfection. She is a recent recipient of an UCLA AIDS Institute grant and, along with colleagues at the University of Cape Town in South Africa, will be examining the role of hepatitis B genotype in HIV and hepatitis B treatment outcomes in HIV/HBV coinfected patients receiving antiretroviral therapy.

Healthcare epidemiology and antimicrobial resistancd, including:

1. Characterizing the clinical and molecular epidemiology of emerging multidrug-resistant health-care associated pathogens;
2. Characterizing risk factors, prevention strategies, and treatment for opportunistic infections among solid-organ and bone marrow transplant recipients;
3. Evaluating the impact of infection control and antimicrobial utilization on antimicrobial resistance and resource utilization in ICUs using microsimulation modeling;
4. Assessing novel infection control technologies;
5. Assessing occupational bloodborne pathogen risk reduction strategies, including the clinical and economic impact of safety devices
   

The major focus of Dr. Abuladze's research is to understand the molecular mechanisms responsible for sodium bicarbonate transport in renal cells.  Using oocyte and mammalian expression systems, the lab has characterized several new members of the sodium bicarbonate cotransporter family including pNBC1 and NBC3.  pNBC1 is responsible for electrogenic bicarbonate secretion in the pancreas but also found in many other tissues.  NBC3 plays an important role in proton/base transport in the collecting duct and mediate electroneutral sodium/bicarbonate cotransport in the collecting duct.  Mutant clones of pNBC1 and NBC3 have been constructed to investigate structure/function relationships of these cotranporter.  Several splice variants of pNBC1 and NBC3 have been found.  The interaction between splice variants is currently being investigated.  The functional significance of the multimeric complexes containing splice variants of various sodium bicarbonate cotransporter is also being studied.  

Since joining UCLA, I have made substantial improvement in the Kidney Transplant Research program.  I have expanded the research office, increasing the number of full time employees from one to four.  Currently I serve as co-principle investigator on 7 active or upcoming patient oriented research grants sponsored by Novartis, Bristol Myers Squibb, Roche, Iconix, and Pfizer, and principle investigator on 5 trials sponsored by Novartis, LifeCycle, and Isotechnika.  In the past year, we have been awarded a total of $850,000 for our research office.

My primary research interests include outcomes registry analysis and clinical trials in kidney transplantation.  During the past 6 years, I have authored and co-authored more than 60 articles in the area of kidney transplantation, including 15 since I joined UCLA last year.  My research focuses on the evaluation of immunosuppressants in transplantation, hepatitis in renal transplantation and the optimal utilization of organs.  The studies I have led have been of key clinical significance in the practice of transplantation medicine.  The study, “Mycophenolate mofetil dose reductions and discontinuations after gastrointestinal complications are associated with renal transplant graft failure” was the first study using Medicare administrative data to evaluate the immunosuppressant prescription fill rate among kidney transplant patients.  It also demonstrated that MMF dose reductions following GI symptoms were associated with a decrease in graft survival.  Since then we have continued to study the important issue of medication compliance and outcomes in kidney transplant patients.  The following study “Retrospective Analysis of Immunosuppression Compliance, Dose Reduction Discontinuation in Kidney Transplant Recipients” was the first to evaluate compliance among national kidney transplant recipients and analyze the relationship with outcomes.  The paper, “Health insurance considerations for adolescent transplant recipients as they transition to adulthood” which reviewed the evidence for the impact of loss of insurance coverage in adolescent transplant recipients was cited in press coverage of the transplant community’s recent dialogue with Congress on improving pediatric Medicare coverage.  Most recently, my abstract entitled, “Kidney Transplantation in the Elderly Recipient Using Deceased Donor after Cardiac Death Organs: An Analysis of OPTN/UNOS Data" was selected by the American Society of Nephrology as a highlighted abstract to be presented to the media during Renal Week 2007.  This study examines outcomes of elderly patients who receive kidney transplants using organs from donors after cardiac death.

In addition, I have spent the last 5 months creating a UCLA kidney transplant research database.  This has been a labor-intensive project which will culminate in the creation and analysis of one of the largest single center kidney transplant databases in the United States.  This database will contain data on more than 2000 patients transplanted in the last ten years and will continue to encompass prospective data from kidney transplants at UCLA.  I will utilize this database for analysis and will submit grants to various organizations to support this activity.   I believe this project is very important and will undoubtedly contribute to the understanding and care of renal transplant patients.

Dr. Danovitch’s transplant-related research has focused on various aspects of clinical transplantation and particularly the development of new immunosuppressive drugs and innovative immunosuppressive protocols. He has been very active on the national level in the development of management guidelines for various aspects of clinical transplant care as well the complex issues associated with organ allocation at a time of acute national shortage.

Dr. Hajmomenian’s academic interest is in the mechanism of renal injury in rheumatologic diseases and the vasculitides.

Our laboratory studies the molecular physiology of acid-base transporters. The lab has contributed significantly to the molecular understanding of bicarbonate transporters and has made key discoveries in the field of bicarbonate transport biology and ion homeostasis.

Since the lab’s discovery of the pancreatic electrogenic sodium bicarbonate cotransporter (pNBC1), the lab has systematicallydetermined the structure-function characteristics NBC1 proteins in studies analyzing:

• The mechanism by which the transporters shift stoichiometry;
• The mechanism of cAMP-induced flux regulation;
• The mechanism by which carbonic anhydrase II (CAII) modulates its function.

The latter studies have demonstrated the CAII and NBC1 form a transport metabolon wherein there is intermolecular transport of bicarbonate between the two proteins thereby significantly enhancing the efficiency of transport.

In addition, the lab has discovered the first electroneutral sodium bicarbonate cotransporter NBC3, and characterized its fundamental role in sensory receptor biology. A knockout mouse model of this transporter published in Nature Genetics, demonstrate that the mouse is an excellent model of Usher’s syndrome, the most common cause blindness and deafness in humans. Although it had previously been believed that the known acid-base transport processes provide a certain biological robustness, the finding that mice lacking NBC3 gradually lose their photoreceptors and have auditory impairment demonstrates the fundamental role this transporter plays in these two sensory organs.

Furthermore, the lab has also characterized the second known electrogenic sodium bicarbonate cotransporter, NBC4. This cotransporter has recently been immunolocalized to the basolateral membrane of hepatocytes. NBC4 is also present in renal uroepithelial cells where it potentially protects the renal medulla from large swings in urinary pH due to changes in dietary intake.

In separate studies in collaboration with M. Nguyen, new equations have recently been developed for analyzing quantitatively, the generation and treatment of the dysnatremias.

Dr. Nguyen’s research interests are in the area of fluid and electrolytes and acid-base physiology. He is particularly interested in disorders of sodium and water balance. His work has focused on defining the determinants of the plasma water sodium concentration as well as elucidating quantitative approaches to analyzing and managing the dysnatremias. In his current research, Dr. Nguyen derived a new mathematical model that can be utilized to predict the equilibrium pH in a multiple buffered aqueous solution and to define the partitioning of excess H+ among the various buffer components. Historically, the Henderson-Hasselbalch equation has been used by chemists to model acid-base chemistry. In recent years, the Stewart strong ion approach has been thought by many investigators to be a superior mechanistic approach to characterizing acid-base disorders due to its purported superiority in modeling acid-base reactions in solutions with multiple buffers that more accurately reflects fluid compartments in vivo. However, pivotal to the Stewart formulation is the purported role of electroneutrality in determining and modifying the pH of a solution. Although the Stewart strong ion approach has been accepted by many investigators to be the new paradigm in acid-base physiology, Dr. Nguyen’s recent work has called into question the superiority and validity of this theory. Indeed, his recent work demonstrated that electroneutrality per se does not mechanistically define the pH of an aqueous solution, and that the Henderson-Hasselbalch and Stewart strong ion approaches are quantitatively identical in determining the pH of a multiple buffered aqueous solution. Dr. Nguyen’s current research demonstrates that neither the Henderson-Hasselbalch nor strong ion model can be used to predict the equilibrium pH of a multiple buffered aqueous solution since their derivations model the behavior of the solution only when equilibrium has already been achieved. In his present research, Dr. Nguyen has derived a new mathematical model that can be utilized to predict the equilibrium pH in a multiple buffered aqueous solution based on pre-equilibrium conditions and that can be used to quantitatively define the partitioning of H+ buffering among the buffer pairs in solution. The validity of this new mathematical model is currently being tested using solutions with various buffer pairs and measuring the pH changes following the addition of HCl.

My interests are in the areas of diabetic nephropathy and cardiac hypertrophy.  Diabetes can cause significant microvascular and macrovascular disease. Forty percent of persons with Type I diabetes and 30-40% of persons with Type II diabetes develop the renal microvascular complication of diabetes known as diabetic nephropathy. Once this develops the disease inevitably progresses to renal failure making diabetes the most common cause of end stage renal disease in the United States. While it is still possible to delay this progression with tight glucose and blood pressure management, there is still no cure. Therefore, the goal of my research is to uncover potential mechanisms involved in this progression that can serve as therapeutic targets. As part of the pathology, the glomerular mesangium expands so that it severely reduces glomerular capillary blood flow and glomerular filtration due to extensive accumulation of extracellular matrix (ECM). The forms the pathologic lesion known as diabetic glomerulosclerosis. Plasminogen activator inhibitor-1 is an important enzyme inhibitor that is significantly upregulated in the diabetic milieu. This increase in PAI-1 transcription correlates with an increase in fibrosis. The goal of this laboratory is to identify and ultimatley target the gene promoter regulatory mechanisms that control PAI-1 expression in rat and human. This involves in vitro transfection, site-directed mutagenesis using PCR, Northern blot analysis and electrophoretic mobility shift analysis as well as in vivo experiments in animals and eventually in human.

 This laboratory is investigating the signaling pathways activated by mesangial cell-ECM adhesion and its effect on the progression of diabetic glomerulosclerosis.

We are currently involved in identification of novel transcriptional elements in the cardiac sodium-calcium exchanger gene promoter that are regulated by alpha-adrenergic stimulation during cardiac hypertrophy.

Dr. Nissenson’s major research interests focus on the quality of care for chronic kidney disease patients including issues of healthcare delivery and economics; anemia management; impact of anemia on brain and cognitive function.  His research has included extensive clinical trials of new devices and drugs related to renal disease, including seminal work with recombinant human erythropoietin (rHuEPO), darbepoietin alfa, and sodium ferric gluconate. Dr. Nissenson is co-principal investigator on a recently obtained NIH Center Grant looking at issues of disparities in healthcare delivery for patients with chronic kidney disease, directing the health outcomes and public policy initiatives.  This project will be carried out in collaboration with Drew Medical School and the RAND Corporation.  In addition, Dr. Nissenson is co-P.I. on an NIH grant looking at benefits and feasibility of providing daily dialysis to patients with ESRD.

Dr. Pham's current areas of research interest include the pathogeneisis of thrombotic microangiopathy in renal transplants.  She is also looking at the effect of mycophenolate mofetil on cardiovascular risk factors, and the clinical role of magnesium in patients with type II diabetes mellitus.

We study the molecular mechanisms of the acute renal failure induced by trichloroethylene and other industrial solvents. It is known that the metabolism of trichloroethylene and other solvents results in the generation of mercapturic acids (N-acetyl-cysteine S-conjugates) which are either secreted in the proximal tubule, or deacetylated and further metabolized into nephrotoxic sulfur-containing reactive fragments. We have cloned the key renal enzyme responsible for deacetylating mercapturic acids derived from trichloroethylene thereby mediating their nephrotoxicity. This enzyme named aminoacylase 3 (AA3) co-localizes in S1 nephron with the multidrug resistance associated protein 2 (Mrp2). We demonstrated that Mrp2 mediates transport of mercapturates. Therefore AA3 may form a complex with Mrp2 on the apical membrane of S1 nephron, which stimulates the transport of mercapturates via Mrp2 whereby protecting this nephron segments from the toxic products of mercapturate metabolism. We are performing structural characterization of AA3, Mrp2 and their complex using cryo electron microscopy and protein crystallography.

Dr Anjay Rastogi finished his Internal Medicine residency and Nephrology fellowship at David Geffen School of Medicine at UCLA. He also has a doctoral degree in Pharmacology which he completed under the mentorship of Nobel Laureate Louis Ignarro also at UCLA. His dissertation was on the role of nitric oxide in inflammation and various factors modulating high output Nitric Oxide production. Dr Rastogi?s current research interests include chronic kidney disease and hypertension. He is currently setting up a multidisciplinary Chronic Kidney Disease Program at UCLA. Dr Rastogi has also been deeply involved in medical education and is the Associate Director of the Nephrology Fellowship training program and is also actively involved in Clinical Pharmacology.

Dr. Wilkinson's research interests are in renal transplant immunosuppression and the long-term prevention of medical diseases in transplant recipients. His transplant research program has taken the lead in introducing into practice several new immunosuppressive drugs and protocols in a cost-effective manner. The research performed by his group has involved multicenter trials investigating the role of Daclizumab dosing in combination with Tacrolimus; the role of Mycophenolate mofetil in maintenance renal transplant patients; the use of Fenoldopam with early CSA in renal delayed graft function. Dr. Wilkinson has also investigated the role steroid withdrawal in renal transplant recipients in a large multi-center trial. In addition to the use of these agents in acute transplant rejection, he is studying the factors responsible for the development of chronic renal transplant rejection, which is a major factor limiting long-term survival. The laboratory has addressed non-allogenic risk factors, such as hyperlipidemia. His group found that pravastatin, when used with cyclosporine, has an added immunosuppressive effect in renal transplant recipients. The mechanisms responsible for this effect are currently being pursued in collaboration with several members of the immunology research unit.

Dr. Wilkinson's other areas of interest include the impact of kidney failure in liver transplant recipients, and the long-term management of hypertension, hyperlipidemia and diabetes mellitus in transplant recipients. He was Chairman of an international committtee that developed and published guidelines for the diagnosis and treatment of new onset diabetes mellitus after transplantation.

The Role of Chemokines and Cytokines during Acute and Chronic Lung Allograft Rejection.  Two in-vivo (Rat orthotopic single lung transplantation and murine heterotopic tracheal transplantation) models and in-vitro models (i.e. mixed leukocyte reactions) are being used.  In addition we are doing work on the role of cytokines during ventilator induced lung injury with a murine model in which mice are placed on a mechanical ventilator.

My basic clinical research is in the general area of exercise physiology, exercise testing, physical fitness and exercise limitations in disease. We have projects ongoing which involve patients with COPD, chemotherapy related anemia, breast cancer with fatigue, scleroderma and beryllium exposure. In normal subjects we are interested in oxygen uptake kinetics.

My research is focused on innate immune responses to bacterial infections in the lung. Currently, we are investigating how prior influenza infections impair antibacterial immune defenses, thereby rendering influenza-infected hosts susceptible to secondary bacterial pneumonias. We are also analyzing how a family of receptors known as Toll-like receptors, which are important for recognizing the presence of infection and activating immune responses, are regulated during sepsis, which may provide insights into why septic patients are at increased risk for nosocomial infections.

Dr. Dubinett conducts translational research in the immunobiology of lung cancer. Building on original discoveries regarding inflammation in human non-small cell lung cancer (NSCLC), he has developed a translational research program, which now utilizes these laboratory-based studies in the clinical setting. His laboratory has identified inflammation-dependent genes and proteins mediating angiogenesis, apoptosis resistance, invasion and immune suppression in NSCLC. His studies focus on the microenvironment, inflammation and epithelial mesenchymal transition in the pathogenesis of lung cancer.

My lab studies innate immunity and the regulation of systemic iron metabolism in humans and in experimental animals. Currently, our main disease targets are anemia of inflammation and diseases of iron overload (hereditary hemochromatosis and iron-loading anemias).

Research lab: Clinical research involving asthma and COPD. Additional areas include HIV associated emphysema, smoking cessation and the effects of marijuana and cocaine on the lungs. Classic clinical drug trials from pharmaceutical companies, single-site investigator initiated studies and more complex projects funded by the NIH are performed with a staff of seven coordinators. Small airways function as assessed by a variety of physiologic and radiographic methods is a specific niche.

PFT lab: Quality assurance and validation of new methods are carried out in the clinical PFT lab

My research is focused on iron metabolism and its disorders. Iron is an essential trace element whose levels must be maintained in an optimal range. Iron deficiency causes cellular dysfunction most frequently manifested by anemia. Iron excess due to genetic causes or blood transfusion causes free radical mediated cell injury and carcinogenesis, manifested as hepatic cirrhosis, heart failure, multiendocrine failure, arthritis and hepatocellular carcinoma.

The master regulator of systemic iron metabolism is the peptide hormone hepcidin. We and others showed that hepcidin functions by inhibiting iron flows into plasma, including the absorption of dietary iron in the intestine, recycling of iron from old erythrocytes by macrophages, mobilization of iron from hepatic stores, and transfer of iron across the placenta. Hepcidin synthesis is homeostatically increased by plasma iron and iron stores, and decreased by erythropoietic activity, thus allowing modulation of iron absorption and recycling according to the body iron needs. At the molecular level, hepcidin acts by inducing degradation of its receptor, the iron channel ferroportin.

We also demonstrated hepcidin’s role as a pathogenic factor in iron disorders. Hepcidin deficiency or the resistance of ferroportin to hepcidin is the cause of all forms of hereditary hemochromatosis. Hepcidin deficiency also contributes to iron overload in patients with hereditary anemias such as beta-thalassemias. In contrast, elevated hepcidin during inflammation and infections contributes to the development of anemia of inflammation by causing iron retention in macrophages and blocking dietary iron absorption. Hepcidin thus may be useful target for improved diagnostics and therapy of iron disorders.

Current areas of interest:

• Mechanisms of hepcidin regulation by iron
• Mechanism of hepcidin dysregulation in iron overload diseases and inflammatory disorders
• Molecular mechanism of hepcidin interaction with ferroportin
• High-throughput screening for hepcidin antagonists and agonists

My lab studies the etiology of anemia of inflammation (anemia of chronic disorders) and anemia of cancer. Specifically, we study the role of hepcidin and IL-6 in limiting iron availability and modulating erythropoiesis. Most of the work is performed in animal models but we are doing some early human studies.

We are involved in both multi-center and investigator-initiated clinical investigations in the areas of lung transplantation and pulmonary arterial hypertension (PAH). Currently, our lung transplant studies include: inflammatory mediators of allograft rejection in bronchoalveolar lavage; effects of bovine surfactant replacement after lung transplantation with acute cellular rejection; nebulized cyclosporin A as prophylaxis for chronic lung rejection (bronchiolitis obliterans syndrome). Our pulmonary hypertension studies focus on the influence of lung inflammation and chemokines on development of disease, as well, novel pulmonary vasodilator protocols including a study of sirolimus (Rapamune) as adjunctive therapy for PAH.

Primary Research Areas:

1) Tumor Immunology and Immunotherapy. 

Our research focuses on the immunobiology of antigen-presenting dendritic cells and their role in stimulating anti-tumor immunity. Projects focus on the differentiation and maturation of dendritic cells, activation and modulation of tumor-specific T cell responses, the use of gene therapy to stimulate vaccine responses, animal models for tumor immunotherapy, and human clinical trials in which new approaches developed in the laboratory are used to treat patients with cancer.  Projects focus on several tumors including lung cancer, prostate cancer and breast cancer.

2) Toxicology of Inhaled Substance Abuse. 

Our research examines tetrahydrocannabinol (the active component of marijuana) and cocaine for their effects on cell function, host immunity and antibacterial defenses, and responses to HIV infection.  One aspect of the laboratory evaluates THC from a toxicology perspective for its effects on gene regulation, apoptosis, cellular energetics and reactive oxygen production using cell based and animal exposure models.  Another project evaluates THC and cocaine for their receptor-specific regulation of immune function, cytokine production, T cell activation and antigen presentation.  These studies employ human blood cells in culture and blood samples collected from control subjects, marijuana users and users of crack cocaine.  In conjunction with a collaborator, we are also evaluating the interaction between these drugs and the susceptibility to HIV using animal models.

3) Clinical Research. 

Our group is involved in several clinical research studies.  One study focuses on the capacity for retinoid compounds to regenerate damaged lung tissue in patients with emphysema.  Another set of studies is evaluating cytoxan as a therapy for patients with scleroderma-related interstitial pulmonary fibrosis.  A third study is evaluating anemia for its impact on the clinical measurement of diffusing capacity.

Primary research areas:

1. Studying the immune system in the settings of sepsis and liver disease, specifically with regards to predisposition to certain types of infections.
2. Studies in the liver transplant intensive care unit including novel treatments of portopulmonary hypertension and factors predicting pulmonary complications in liver transplantation.
3. Clinical research involving asthma and COPD in collaboration with the Kleerup/Tashkin laboratory.

Dr. Weigt cunducts clinical and translational research on the role of infections in lung allograft dysfunction.

Minocycline Treatment in Patients with Idiopathic Pulmonary Fibrosis - a Pilot Study (Investigator: Eric Kleerup, M.D. and David Zisman, M.D.; Sponsor: UCLA SCOR on the Pathobiology of Pulmonary Fibrosis)
A randomized, double-blind, placebo-controlled study to determine the efficacy and safety of minocycline in patients with Idiopathic Pulmonary Fibrosis (IPF). Minocycline could prevent the overgrowth of small blood vessels (angiogenesis) and delay the progression of idiopathic pulmonary fibrosis (IPF). Randomization will be 1:1 active-to-placebo ratio. Duration of study will be 48 weeks.

The INSPIRE Trial: A Study of Interferon gamma-1b for Idiopathic Pulmonary Fibrosis (IPF) (Investigator: David Zisman, M.D; Sponsor: InterMune Pharmaceuticals)
A phase 3, randomized, double-blind, placebo-controlled trial to determine the efficacy and safety of 200 ?g of recombinant Interferon gamma-1b administered by subcutaneous (SC) injection, compared with placebo, in patients with IPF. Interferon gamma-1b may improve survival in patients with mild to moderate IPF. Randomization will be 2:1 active-to-placebo ratio. Duration of study will be 2 years active drug or placebo (rescue therapy will be permitted for patients who meet predefined criteria).

Efficacy and safety of oral bosentan in patients with Idiopathic Pulmonary Fibrosis (Investigator: David Zisman, M.D; Sponsor: Actelion Pharmaceuticals)
Endothelin-1 (ET-1) is expressed in a variety of pulmonary pathological conditions including pulmonary vascular disease and pulmonary fibrosis. Bosentan (an oral dual ET-1 receptor antagonist) could delay the progression of idiopathic pulmonary fibrosis (IPF), a condition for which no established treatment is available. The present trial investigates a possible use of bosentan, which is currently approved for the treatment of symptoms of pulmonary arterial hypertension (PAH) to a new category of patients suffering from IPF.

A Safety and Efficacy Study of Sirolimus in Patients with Idiopathic Pulmonary Fibrosis - a Pilot Study (Investigator: David Zisman, M.D; Sponsor: UCLA SCOR on the Pathobiology of Pulmonary Fibrosis)

The objective of this study is to determine the safety and efficacy of sirolimus compared to placebo on pulmonary function and resting gas exchange in patients with idiopathic pulmonary fibrosis (IPF). Sirolimus could prevent the overgrowth of small blood vessels (angiogenesis) and delay the progression of idiopathic pulmonary fibrosis (IPF). We believe that this drug will result in stabilization or improvement in pulmonary function and/or resting gas exchange over 48 weeks as compared with placebo. The study was designed as a randomized, double-blind, placebo-controlled study of 32 patients. Eligible patients are randomly assigned, in a 1:1 ratio, to receive either sirolimus or placebo daily for 12 months.

Sildenafil Treatment in Patients with Idiopathic Pulmonary Fibrosis and Pulmonary Hypertension- a Pilot Study (Investigator: David Zisman, M.D; Sponsor: UCLA SCOR on the Pathobiology of Pulmonary Fibrosis)

The objective of this study is to demonstrate that a single dose of sildenafil improves exercise capacity in patients with idiopathic pulmonary fibrosis (IPF) and pulmonary hypertension. We believe that this drug will result in an increase in distance walked in subjects with IPF and pulmonary hypertension as compared with placebo. This study was designed as a placebo-controlled study of sildenafil and its effect on distance walked, shortness of breath, and blood oxygenation. Eligible patients will be randomly assigned, in a 1:1 ratio, to receive either sildenafil or placebo.

• Studies of clinical interventions in osteoarthritis
• Biomarkers of osteoarthritis

• Animal model of rheumatoid arthritis: testing of proposed new therapies
• Current focus on influence of peptides designed to improve lipid function
• Experiments to prevent angiogenesis in the synovium

• Pathogenesis of accelerated atherosclerosis in patients with rheumatoid arthritis – focus on lipid abnormalities.
• Identification of biomarkers of disease activity and severity in patients with RA.

• Mechanisms by which antibodies to phospholipids cause clotting – primarily human materials
• New antibodies that cause clotting and/or atherosclerosis in patients with SLE or anti-phospholipid syndrome.

• Clinical trials in scleroderma
• Analysis of clinical features and response to therapies in scleroderma: emphasis on pulmonary interstitial disease and pulmonary hypertension.

• Health economics: the effects of payer rules on utilization of services following major surgeries, focus on joint replacements
• Racial and Gender differences in agreeing to surgeries such as total joint replacements – strategies to correct disparities – uses national databases.

• Multiple clinical trials in patients with rheumatoid arthritis
• Multiple clinical trials in patients with scleroderma
• Analysis of databases of large numbers of patients with scleroderma who have entered clinical trials
• Pharmacology of small molecules used for treatment of rheumatoid arthritis, and of biologics used for many rheumatic diseases.

• Osteoporosis in the general population and in patients with rheumatic diseases. Metanalysis of current therapeutic strategies.
• SLE database of a few hundred patients seen recently at UCLA – studies the basis for atherosclerosis and other complications of the disease.
• Clinical trials in patients with SLE – studies new biologics that specifically target molecules involved in disease pathogenesis.

• Development of novel therapies for SLE – focus on immune tolerance, tolerizing peptides, autoreactive T cell functions, preparation of gene therapies – uses both murine and human materials.
• Understanding the basis of accelerated atherosclerosis in people with SLE – focus on abnormal lipids, abnormal monocyte functions – primarily human studies.

• Quality of life in people with scleroderma; influence of therapies and of disease manifestations.
• Analysis of databases of large numbers of patients with scleroderma enrolled in multicenter trials in the USA
• Treatment of gastrointestinal disease in patients with scleroderma
• Clinical trials in RA, scleroderma

• Studies of the role of the lipokine, leptin, in autoimmunity – uses both human and murine materials.
• Studies of the development, function, and mechanisms of action of regulatory T cells (CD4+CD25+Foxp3+) that suppress autoimmunity - uses both human and murine materials, focuses on SLE.

• Mechanisms underlying accelerated atherosclerosis in patients with SLE – focus on abnormal lipids, particularly pro-inflammatory HDL.
• Analysis of database of a few hundred SLE patients seen at UCLA.
• Abnormalities in monocytes of patients with SLE and atherosclerosis that might account for damage to arterial walls.

• Studies of patients with early rheumatoid arthritis – predictors of various outcomes
• Analysis of large databases of patients with RA enrolled in USA multicenter trials and in the Western Consortium of Rheumatologists group founded by Dr Paulus.

• Health outcomes in elderly patients with RA compared to younger patients – are responses to therapy different?
• Differences in disease characteristics according to age in patients with rheumatoid arthritis.
• Analysis of current measures of disease “remission” – do they correlate with MRI evidence of continuing joint inflammation? When is remission truly remission?
• Analysis of large databases of patients with RA from national multi-center studies.

My laboratory is interested in understanding the pathogenetic mechanisms of immune-mediated inflammatory diseases such as systemic lupus erythematosus (SLE) and scleroderma, with ultimate goals to develop novel immune therapies and to establish novel surrogate biomarkers to diagnose and predict subsets, staging, and progression of these diseases. We use animal models of these diseases to develop concepts and then try to translate this knowledge on to human disease using samples from patients.

1. Dendritic cell migration, skin gamma delta T cells, and skin Langerhans cells in inflammatory skin diseases;
2. Sex chromosomes and hormones in the development of autoimmune diseases (in collaboration with Drs. Voskuhl and Arnold);
3. Mechanisms and biomarkers for lupus nephritis, especially the role of type 2 cytokines and growth factors such as TGF beta;
4. Mechanisms and biomarkers for scleroderma lung and skin disease (in collaboration with Drs. Furst, Khanna, Roth, and Wong);
5. Hematopoietic and mesenchymal stem cell abnormalities;
6. T cell signaling, anergy and tolerance;
7. Self peptide specific regulatory and suppressor T cells;
8. Innate immune cells - marginal zone B cells and natural killer T (NKT) cells;
9. CD1d and lipid-reactive T cells.

• Genetics of human SLE: studies to identify predisposing and protective genes, studies to define importance of gene copy numbers, influence of genes on production of protein products.
• Genetics of human rheumatoid arthritis: studies to identify predisposing and protective genes and genes which promote earlier onset or affect disease severity.
• Development of a mouse model of SLE with atherosclerosis and osteoporosis

• Pathogenesis of spondyloarthropathies – how is inflammation influenced by the HLAB27 haplotypes?