Research Track Faculty Mentors and Research Descriptions

Trainees in the Research Track will have the opportunity to work with mentors located at Columbia University Medical Center (CUMC), Weill-Cornell Medical Center (WCMC) or Rockefeller University (RU), which is next door to WCMC. All of these mentors have successful track records in the training of research fellows. The faculty mentors and brief descriptions of the research are provided:

Paul D. Berk, M.D. (CUMC): The Berk laboratory focuses on mechanisms for the cellular uptake of organic anions, with a particular focus on long chain free fatty acids (FFA). Although FFA uptake was long considered a purely passive and therefore relatively uninteresting process, the laboratory has shown that cellular FFA uptake involves a combination of both facilitated transport and passive diffusion, with the facilitated process predominating at basal plasma FFA concentrations. The first FFA transporter, designated plasma membrane fatty acid binding protein (FABPpm) was also isolated from this laboratory. FABPpm has proven identical to the mitochondrial isoform of aspartate aminotransferase (mAspAT). Current work centers on (1) defining the physiologic and clinical implications of protein-mediated facilitated FFA transport and (2) on determining how mAspAT functions as a plasma membrane FFA transporter.

The Berk laboratory has also documented that tissue specific up-regulation of FFA uptake in adipose tissue is a very early step in the cascade of metabolic abnormalities observed in rodent models of obesity and non-insulin dependent diabetes mellitus (NIDDM), and is associated with specific transcriptional up-regulation of mAspAT. Ongoing studies in obese and non-obese patients indicate that similar phenomena occur in human obesity and NIDDM. Investigations have also centered on the contribution of FFA uptake processes to the evolution of fatty liver. Although histologically similar fatty liver occurs in numerous settings, including obesity, diabetes, high fat diets, and alcohol abuse, hepatocellular FFA uptake is upregulated only in the setting of alcohol abuse. Thus, the pathogenesis of fatty liver varies with the underlying etiology. Pulse-chase immunoprecipitation experiments and studies of the intracellular disposition of mAspAT/green fluorescent protein (GFP) fusion protein are being used to define the intracellular trafficking pathways that bring mAspAT to the plasma membrane. Molecular modeling of mAspAT crystal coordinates are being employed to identify a possible FFA binding site within its tertiary structure. The significance of this site is being studied experimentally by examining the binding of FFA to expressed/purified binding site mutants and the effects on FFA uptake of the expression of various binding site mutants in transfected cells.

David A. Brenner, M.D. (CUMC): The overall goal of the research in the Brenner Laboratory is to study the regulation of gene expression in the liver and intestines under normal and pathological states and applying modern molecular biological techniques to the study of gastrointestinal diseases. With transcriptional regulation being the unifying theme of his research, research in the Brenner Laboratory can be divided into two general areas.

Molecular pathogenesis of cirrhosis: Cirrhosis of all etiologies is characterized by a marked increase in the deposition of type 1 collagen, which results in part from increased transcription of the collagen genes and in part from increase in the stability of the collagen mRNAs. To define the mechanisms regulating collagen genes transcription in the liver, the laboratory is defining the regulatory region in the type 1 collagen alpha 1(l) gene and the DNA binding proteins interacting with these genes. Furthermore, the mRNA binding proteins that stabilize the alpha 1(l) mRNA are being identified and characterized using in vitro decay assays and siRNAs. The results are investigated using primary cultures of hepatitic stellate cells derived from patients with liver diseases and from transgenic mice. The relationship between stellate cell activation, stellate cell apoptosis and fibrogenesis is being characterized in mouse models of liver disease and in primary cultures. Recently, the laboratory has concentrated on developing models of alcohol induced fibrosis and hepatitis C virus-induced fibrosis.

Regulation of signaling in the liver: The Brenner Laboratory has demonstrated the induction of the oncogene c-Jun, a constituent of the AP transcription complex, and the transcription factor NF-kappa B during hepatic regeneration and during the acute phase response in vivo and growth reinitiation in primary cultures of adult hepatocytes. Primary cultures of hepatocytes from rats and transgenic mice are used as a model to study aspects of hepatic gene regulation. These studies have demonstrated that the c-Jun kinase, JNK, is pro-apoptotic during hepatocyte activation due to unknown downstream substrates. On the contrary, NF-kappa B activation is anti-apoptotic through the induction of several NF-kappa B responsive genes including those encoding iNOS, Bcl-XL, XiAP. The cross talk between these critical signaling pathways is being investigated.

Andrew J. Dannenberg, M.D. (WCMC): The primary focus of the Dannenberg Laboratory is developing novel approaches in the prevention or treatment of cancer with special emphasis on cyclooxygenase-2 (COX-2), the inducible form of COX. A multifaceted approach is used to investigate this question.

COX-2 overexpression in cancer: One aspect of the work in the Dannenberg Laboratory aims at identifying human diseases in which COX-2 is overexpressed. For example, his laboratory showed that COX-2 is overexpressed in a variety of cancers and premalignant lesions. These analyses utilize human tissues and rely on a combination of molecular and immunological approaches, including immunohistochemistry, immunoblotting and quantitative reverse transcription-polymerase chain reaction.

Signal transduction pathways and COX2 expression: A second goal of the laboratory has been to identify signal transduction pathways and molecules that control COX-2 expression. Emphasis has been placed on defining the mechanisms by which oncogenes (Ras, Wnt, HER-2/neu), tumor suppressor genes (p53) and tumor promoters (bile acids, phorbol esters) modulate COX-2 transcription. The Dannenberg laboratory was among the first to show the importance of specific mitogen-activated protein kinases (p38, ERK1/2, JNK) in regulating COX-2 expression. In addition to ongoing transcriptional studies, the Dannenberg Laboratory is actively investigating the molecular mechanisms that control COX-2 message stability. This includes studies to identify RNA binding proteins such as HuR that affect the stability of COX-2 mRNA.

COX2 in human disease: Research is also ongoing to extend pertinent in vitro findings to human inflammatory (inflammatory bowel disease) and neoplastic (colon cancer) conditions. Pharmacological approaches to alter message stability are also under investigation. Another goal of the laboratory is to define the mechanisms by which small molecules with chemopreventive properties including dietary components (for example, retinoids, phenolic antioxidants, triterpenoids, fatty acids) block the activation of COX-2 gene expression. To enhance this line of investigation, a COX-2 promoter-based high throughput screen has been developed. The discovery from the Dannenberg Laboratory that microtubule interfering agents, including taxanes, induce COX-2 by modulating both transcription and message stability has provided the rationale for several ongoing clinical trials to determine whether combination therapy with selective COX-2 inhibitors will augment the antitumor activity of taxanes.

Experimental therapeutics: The above studies are complemented by experimental therapeutics approaches to evaluate the potential utility of COX-2 inhibitors alone or in combination with other agents. For example, data from preclinical studies using animal tumor models will determine if inhibitors of epidermal growth factor tyrosine kinase in combination with COX2 inhibitors merit evaluation in clinical studies. These pharmacological approaches are currently being complemented by studies involving knockout mice. In addition, the Dannenberg Laboratory is involved in a series of translational studies, including studies of selective COX-2 inhibitors, in subjects at increased risk for gastrointestinal malignancies such as Barrett esophagus.

Eicosanoid biology applied to human disease: The involvement of distal synthases (for example, microsomal prostaglandin E (PGE) synthase-1 and thromboxane synthase) of the eicosanoid pathway in human disease is another area of active interest. Studies of gastric cancer, colon cancer and inflammatory bowel disease are under way. The role of different prostaglandin receptors in mediating the tumor promoting properties of PGE2 is being investigated both in vitro and in vivo. The mechanistic link between specific endogenous and exogenous factors and arachidonic acid metabolism is also being explored. Specifically, research is being carried out to investigate the link between specific genetic polymorphisms, tobacco smoke and prostaglandin biosynthesis.

Richard J. Deckelbaum, M.D. (CUMC): The major focus of the Deckelbaum Laboratory is to determine regulatory mechanisms for cell-lipid particle interaction and cell cholesterol and triglyceride metabolism. Using cellular and animal model studies, current projects are defining the effects of lipid particle properties on their metabolism via receptor-mediated and receptor-independent pathways. The Deckelbaum Laboratory has demonstrated that substantial amounts of lipoproteins and lipid emulsions can enter cells by receptor independent pathways. Focusing on genes that affect triglyceride and cholesterol homeostasis, the Deckelbaum Laboratory is examining how different lipids, especially free fatty acids and various sphingolipids, modulate sterol regulatory element binding protein (SREBP)-mediated gene expression. Major areas of interest that are currently being explored are summarized below.

The role of particle size and triglyceride fatty acyl composition: The effects of these on modulating interaction of model lipid emulsions or triglyceride-rich particles with apoprotein E and subsequent effects on cell and tissue metabolism in vitro and in vivo using mouse models are being pursued. In both cell and animal models, The Deckelbaum Group is demonstrating that triglyceride-rich particles enriched in long chain omega-3 triglycerides do not enter tissues via classic receptor-dependent pathways but rather via other mechanisms which might relate to binding via non-receptor domains on the cell surface through the processes of phagocytosis or pinocytosis.

The role of free fatty acids in lipid metabolism: Free fatty acids may be potent regulators of critical steps in cell lipid metabolism via inhibition of protein expression mediated by sterol regulatory elements in the promoter regions of genes involved in lipid metabolism. Major emphasis has been directed towards determining cellular and molecular mechanisms responsible for these activities of free fatty acids. The laboratory has shown that free fatty acids affect cellular cholesterol partitioning, which affects SREBP cleavage, and alters cellular sphingolipid metabolism to affect SREBP cleavage. Finally, distinctly different mechanisms come into play whereby free fatty acids and cholesterol affect SREBP cellular trafficking.

The role of the intestine in absorption: Studies have been recently expanded to include the role of the intestine in absorption and packaging different fatty acids (as chylomicrons) with downstream effects on expression of lipid metabolism related genes.

Dr. Deckelbaum also coordinates programs related to the effects of varying nutrient intakes on expression of cardiovascular risk factors in children of different genetic backgrounds. Overall, an important objective of his research program is to develop investigators who can translate basic nutritional questions into basic lipid and cellular biology.

Michael D. Gershon, M.D. (CUMC): Research in the Gershon Laboratory is focused on the enteric nervous system (ENS), the intrinsic innervation of the bowel. This is the only part of the peripheral nervous system that is capable of mediating reflex behavior in the absence of input from the brain or spinal cord. The goals of the research in the Gershon Laboratory are to understand the organization of the two neural plexuses that comprise the ENS and to determine how enteric microcircuits and the activity of individual neurons within these circuits control the primitive motile, secretory and absorptive behaviors of the gut. His laboratory has devised novel techniques to study enteric microcircuits. In addition to electro-physiology, these include optical imaging techniques with probes that permit neuronal activity to be assessed and neuronal connections to be identified. The Gershon Laboratory also studies the cellular biology and function of serotonin in initiating enteric reflexes and signaling to the brain. These studies include the analysis of the behavior of the gut in transgenic mice that lack individual subtypes of serotonin receptor and/or the transporter molecule that is primarily responsible for the inactivation of serotonin within the bowel.

In addition to studies of the adult ENS, the Gershon Group is investigating its development. The ENS is derived from precursors that migrate to the gut from the neural crest. His laboratory is currently identifying the molecular signals (guidance molecules and growth factors) utilized in the process. What are the cues that assist the precursors to migrate correctly from their neural crest origin to their final destinations in the bowel? Why do the precursors stop migrating when they reach these destinations? And what are the microenvironmental cues that influence the phenotypic expression of neural and glial precursors within the ENS? The research involves tissue and organ culture and the construction of chick-quail interspecies chimeras. The laboratory is also determining the molecular basis of a defect in a mutant strain of mouse that causes a segment of bowel not to be colonized by crest-derived precursors.

Stephen P. Goff, Ph.D. (CUMC): Research in the Goff Laboratory can be divided into three broad areas.

Replication of mammalian retroviruses: These include the human immunodeficiency virus and Moloney murine leukemia virus. The major approach has been to alter cloned DNA copies of the viral genome by site-directed mutagenesis, and to determine the effects of these mutations on the viral life cycle after expressing them in mammalian systems. These genetic analyses have defined the functional domains of various viral proteins and the sites of their action on viral nucleic acids. The Goff Laboratory has also expressed reverse transcriptase and integrase in bacteria and studied these enzymes biochemically.

Interaction between viral and host proteins: The Goff Laboratory has applied the yeast two-hybrid system to monitor protein-protein interactions between viral proteins, and to identify new host proteins that interact with the gag, pol and env gene products. A relatively new project in the Goff Laboratory is to study the interactions between hepatitis C viral proteins and cellular components and to determine how these interactions affect viral replication.

The role of viral oncogenes: The Goff Laboratory is also interested in the functions of several viral oncogenes, especially the tyrosine kinases v-abl and v-src, and other signal transduction molecules, including the axl/ark receptor kinase; mpl, the thrombopoietin receptor; pdeg, the retinal cGMP phosphodiesterase; and other cytokine receptors. Embryonic stem cell technologies are being used to generate knock-out mice deficient in these transduction molecules.

Lorraine J. Gudas, Ph.D. (WCMC): Retinoids, which include both natural and synthetic derivatives of vitamin A, have a variety of effects on normal cell differentiation and on the process of carcinogenesis, including in the liver and the gastrointestinal tract. Retinoids are used clinically in the treatment of a number of diseases, including cancer, skin conditions such as acne and psoriasis, and emphysema. The responses of many cell types to retinoid treatment are mediated initially by intracellular retinoid receptors and involve changes in gene expression, cell growth, and cell differentiation. This laboratory is studying how retinoids elicit these dramatic changes in cells through the identification and analysis of the genes which are regulated by retinoids. These genes include Rex1, a stem cell marker and transcription factor which is transcriptionally repressed by retinoids, and homeobox genes, which encode transcription factors important in embryonic cell differentiation. The laboratory has identified retinoic acid responsive "enhancers," or DNA control regions, 3' of homeobox genes called Hoxa-1 and Hoxb-1. The Gudas Laboratory has shown that these enhancers activate expression of these Hox genes in response to retinoic acid both in cultured cells and in transgenic mice. The laboratory is now in the process of generating mice in which these enhancers are relocated to a more 5' chromosomal position in the Hox gene cluster by gene targeting so that the functions of these retinoid-regulated enhancers can be studied in a mouse model.

Other projects in the laboratory include the analysis of the expression and functions of the intracellular retinoid binding proteins CRABP-I and CRABP-II; the study of the effects of the cyclic AMP signaling system on retinoid regulated genes; the analysis of various retinoid analogs in the treatment of human oral squamous cell carcinomas (epithelial tumors of the head and neck), prostate, breast, renal, and bladder carcinomas; and the identification of new retinol (vitamin A) metabolites in specific cell types such as epithelial and neuronal cells. The Gudas Laboratory has developed an improved model of mouse oral cavity carcinogenesis and is using this model system to test new therapies employing retinoic acid plus histone deacetylase inhibitors. These therapies are also being tested in kidney and bladder cancer patients in clinical trials conducted at the Weill Medical Center of Cornell University. Collectively, these studies should lead to new insights into the roles of retinoids in the regulation of cell growth and differentiation and to new treatments for diseases.

Alfred I. Neugut, M.D., Ph.D. (CUMC): Research in the Neugut Group has centered almost exclusively on cancer epidemiology and prevention. He initiated a series of important studies, which continue today, that focused on risk factors for the occurrence and recurrence of colorectal adenomatous polyps (adenomas). These studies were responsible for generating awareness of colorectal cancer using colonoscopy and fecal occult blood testing for routine screening and diagnosis. Another of his research focuses on the occurrence of second malignancies following radiation therapy. For example, Dr. Neugut has found elevated risks of lung cancer and esophageal cancer following breast cancer radiotherapy and of bladder cancer following prostate cancer radiotherapy. Other areas of cancer epidemiology to which he has made contributions include cancers of the small bowel, gallbladder and biliary tree.

A part of Dr. Neugut's research is also centered on studying the use of chemotherapy and radiotherapy for cancer in the elderly. Education of community physicians regarding cancer prevention and control through academic detailing methods, racial/ethnic variations in attitudes towards cancer and screening and aspects of the use of complementary and alternative medicine are also current research interests.

Charles M. Rice, Ph.D. (RU): Research interests in the Rice Laboratory center on animal RNA virus replication and pathogenesis. His laboratory studies alphaviruses, such as Sindbis virus, as convenient models for understanding mechanisms regulating RNA virus replication and transcription. These small RNA viruses have also been engineered and adapted to provide a set of tools for gene expression, gene therapy and vaccination. In the flavivirus family, projects involve the classical mosquito-borne agents such as yellow fever virus and West Nile virus, the animal pestiviruses and hepatitis C virus. For hepatitis C, studies focus on the organization, expression, and functions of the viral proteins. Dr. Rice discovered a novel highly conserved RNA element at the 3’ end of the genome and produced the first functional cDNA clone of this virus. His laboratory has recently established efficient cell culture systems for studying hepatitis C virus RNA replication and evaluating antiviral efficacy. Current work is aimed at optimizing cell culture assays, investigating alternative animal models, and defining new viral targets for possible therapeutic intervention. Using the chimpanzee model, members of the Rice laboratory also study the interactions between hepatitis C virus and the host immune system.

Dr. Rice is also Executive Director of the Tri-institutional Center for the Study of Hepatitis C, a cooperative program between the Rockefeller University, Weill Medical College of Cornell University and New York-Presbyterian Hospital. Members of the Center for the Study of Hepatitis C investigate many aspects of hepatitis C virus-associated pathogenesis and liver disease. Examples include i) phenotyping cells in the liver that support active hepatitis C virus replication, ii) use of the replicon system to study virus-host interactions that may contribute to fibrosis progression, iii) characterization of dendritic cell function in hepatitis C virus-infected patients to understand possible defects in adaptive immune responses, iv) characterization of B cell and immune complex-related extrahepatic manifestations of chronic hepatitis C, and v) study of molecules involved in hepatitis C virus entry and neutralizing antibodies. The Center for the Study of Hepatitis C training environment brings together outstanding basic scientists, clinical investigators and translational scientists with interests in liver disease.

Edward H. Shortliffe, M.D., Ph.D. (CUMC): Recent trends in health care delivery have led to an increased emphasis on the development of guidelines for prevention, diagnostic workup, treatment and patient-management processes (clinical pathways). Such guidelines are motivated by concerns about marked variations in clinical practice and are designed to help provide a common standard of care both within a health care organization and among different organizations. Interests of the Shortliffe Group include the broad range of issues related to integrated decision-support systems, their effective implementation, promotion of the computerization of guidelines and the role of the Internet in healthcare. He has been Principal Investigator of the InterMed Collaboratory, a joint project of biomedical informatics laboratories at Harvard (the Decision Systems Group at Brigham and Women's Hospital), Stanford, and Columbia Universities. InterMed collaborators have created the GuideLine Interchange Format (GLIF), a specification for structured representation of guidelines (see www.glif.org). The goal of GLIF is to facilitate sharing of clinical guidelines by providing a specification for their representation in a computer-interpretable form that is intended to be precise, non-ambiguous, human-readable, and independent of computing platforms (to facilitate sharing). The Shortliffe Group has also emphasized the development of an execution engine that will allow the integration of GLIF-encoded guidelines with operational clinical systems, such as results-reporting systems and physician order-entry systems.

Manikkam Suthanthiran, M.D. (WCMC): A major focus of research in the Suthanthiran Laboratory is the development of pancreatic islet transplantation for the treatment of type 1 diabetes. The overall goal of the research efforts is to identify clinically applicable gene therapy strategies that will facilitate allogeneic human islet transplantation without long-term immunosuppressive therapy. Preclinical models of islet transplantation have already been established by the laboratory and FDA approval has been obtained for the initiation of a clinical islet transplantation program.

Mechanism of Islet Graft Acceptance: Mouse Islet Transplantation Model: The overall objective of this project is to develop an ex vivo genetic modification strategy that will constrain autoimmunity and alloimmunity and facilitate permanent islet graft survival without exogenous immunosuppressive therapy. Specifically, the project investigates the following:

• The efficacy of the immunoregulatory gene TGF-beta1 to facilitate permanent engraftment of mouse islets will be examined. Islets will be ex vivo genetically modified to express TGF-beta1, and the ability of this transgene to prevent islet destructive autoimmunity, alloimmunity or autoimmunity plus alloimmunity will be examined. The laboratory will also determine whether ex vivo genetic modification engenders tolerance to allogeneic islet grafts.
• The efficacy of angiogenic and anti-apoptotic genes to facilitate islet graft survival will be examined. Islets will be ex vivo modified to express VEGF or Bcl-2, and transplanted along with dendritic cells modified to express TGF-beta1

Ex vivo genetic modification of islets: This strategy is employed to reduce islet mass needed to accomplish insulin independence and to prevent immune destruction. The overall objective of the project is to identify clinically applicable gene therapy strategies that will facilitate allogeneic human islet transplantation without long-term immunosuppressive therapy. The hypothesis that ex vivo genetic modification of allogeneic human islets will reduce the islet mass needed to accomplish sustained insulin independence and prevent their immune destruction in type 1 diabetic patients will be explored by mechanistically linked non-human primate islet transplantation experiments and human islet transplantation trials. Specifically the project will evaluate the following:

• A pilot trial of solitary islet transplantation in type 1 diabetes patients using the steroid free Edmonton protocol. This study, in addition to being the ultimate test of an ability to isolate clinical grade islets, will ensure evaluation of efficacy of ex vivo genetic modification strategies in the absence of concerns regarding the clinical worthiness of the human islets isolated in the Suthanthiram Laboratory. Data from this study will provide independent confirmation of the excellent outcome recently observed with the Edmonton protocol.
• The hypothesis that ex vivo genetic modification of allogeneic islets will: (1) reduce the islet mass required to accomplish insulin independence; and (2) prevent islet destruction from immune mechanisms. This postulate will be tested using diabetic (streptozotocin-induced) cynomolgus monkey (Macaca fascilularis) as the recipient of genetically modified allogeneic islets. The laboratory will determine whether ex vivo genetic modification of monkey islets to express the angiogenic gene, vascular endothelial growth factor (VEGF) or the anti-apoptosis gene Bcl-2 will reduce the islet mass needed to accomplish insulin independence. Whether modification of the islets to express the immunoregulatory gene transforming growth factor-beta1 (TGF-beta1) facilitates islet graft survival and obviates the need for exogenous immunosuppressive drugs will also be examined.
• Investigations that will determine whether ex vivo genetic modification of human islets to express VEGF or Bcl-2 permits a reduction in the islet mass required to accomplish insulin independence in type 1 diabetic patients will be ongoing. The laboratory will also determine whether genetic engineering of human islets to express TGF-beta1 permits complete withdrawal of immunosuppressive drugs in type 1 diabetic patients.
• Mechanistic studies to resolve islet graft destructive mechanisms from islet accommodative mechanisms will also be conducted.

Timothy C. Wang, M.D. (CUMC): Research in the Wang Laboratory is centered on understanding the role of inflammation and growth factors in the development of gastrointestinal cancers. The research program encompasses five major funded projects: 1) Mouse models of gastric cancer - this project investigates the role of gastrin and other hormones/cytokines in the promotion of gastric cancer in response to Helicobacter infection in the mouse. 2) Function and regulation of trefoil factor 2 (TFF2) - this project examines the role of TFF2 in immune responses to Helicobacter and identification of the receptors involved. 3) Regulation of histidine decarboxylase (HDC) and histamine in the stomach - histamine is a downstream target of gastrin and regulates not only acid but also growth/immune responses. This project analyzes the transcriptional and post-transcriptional regulation of HDC, and characterizes its role in growth and immunity of the stomach. 4) Gastrin and colon cancer - this project studies the transcriptional regulation of gastrin by oncogenic (Wnt, Ras, TGF-beta) pathways and examines the role of incompletely processed gastrins (progastrin) in colon cancer pathogenesis. In this project, the role of progastrin in stem cell proliferation will be studied, and novel receptors for progastrin will be cloned and characterized. 5) Mouse models of gastric and esophageal cancer - this is a collaborative project involving MIT, University of Pennsylvania, University of Massachusetts and Vanderbilt University and involves the development of new paradigms regarding the origins of epithelial cancers. Dr. Wang has also been active in developing and studying disease management programs in dyspepsia. Dr. Wang serves as a Co-PI on additional projects involving the role of pathogen recognition receptors in the innate immune response to Helicobacter pylori.

Howard J. Worman, M.D. (CUMC): The Worman Laboratory is primarily interested in determining how mutations in proteins of the nuclear envelope inner nuclear membrane cause a wide variety of inherited diseases. The nuclear envelope is composed of the nuclear membranes, the nuclear pore complexes and the nuclear lamina. The higher order structure of chromatin is influenced by its interactions with this organelle and nuclear envelope proteins may play a role in the regulation of gene expression. Over the years, the Worman Laboratory has characterized several nuclear envelope proteins and their genes and continues to examine their functions.

The long-term, health-related relevance of this work concerns the role of the nuclear envelope in human disease. Mutations in LMNA, a gene that the group characterized a decade ago and encodes lamins A and C, cause several diseases, including Dunnigan-type partial lipodystrophy, autosomal dominant Emery-Dreifuss muscular dystrophy and Hutchinson-Gilford progeria. Dunnigan-type partial lipodystrophy is characterized by loss of peripheral adipocytes, insulin resistance and excessive fat accumulation in the liver. Part of the laboratory’s focus is to determine how mutations in lamins A and C cause these metabolic and hepatic abnormalities.

Mutations in other nuclear envelope proteins cause other diseases. Emerin, an integral protein of the inner nuclear membrane, is mutated in X-linked Emery-Dreifuss muscular dystrophy. Heterozygous mutations in LBR, another integral protein of the inner nuclear membrane protein, cause Pelger-Huët anomaly and homozygous mutations cause a developmental abnormality with sterol reductase deficiency. The Worman Laboratory is also studying how MAN1, another integral protein of the inner nuclear membrane not yet associated with a disease, modulates signaling by TGF-beta.

Methods used in the Worman Laboratory to study nuclear envelope proteins and how mutations in these protein cause disease include in vitro interaction assays, targeting and protein dynamic studies in transfected cells, analysis of gene expression using microarrays and the generation and characterization of transgenic mice. Secondary interests of the Worman Group include the characterization of autoantibodies that recognize nuclear envelope proteins in subjects with primary biliary cirrhosis, primary sclerosing cholangitis and ulcerative colitis and studies on the interactions of hepatitis C viral proteins with cellular components.

Last Updated July 16, 2004