ACGME Fellowship Program - Research Preceptors
Graeme I. Bell, Ph.D.
Dr. Bell is a leading authority on the genetics of diabetes mellitus and directs a program to identify genes that cause diabetes and determine how mutations in these genes affects cell function. The program involves close interactions between basic scientists, clinical investigators and physicians allowing translation of research findings from the bench to the bedside. There are learning opportunities for trainees interested in basic research as well as those interested in clinical investigation and translational research
Matthew Brady, Ph.D.
Dr. Brady is studying insulin metabolic signaling in adipose tissue, using cell lines and primary rodent and human adipocytes. We are particularly interested in the regulation of glucose and lipid storage in adipocytes, and the connection between adipocytic energy metabolism, obesity and the development of insulin resistance and metabolic syndrome.
Currently, there are three main projects in the lab. The first involves studying the impact of altering glycogen metabolism on energy metabolism and adipocyte function. Our protein of interest is called Protein Targeting to Glycogen (PTG), which assembles the rate limiting enzymes in glycogen metabolism with their immediate upstream regulator protein phosphatase-1. We are using adenoviral system to overexpress wild type, dominant negative and shRNA PTG constructs to modulate glycogen metabolism in 3T3-L1 adipocytes. These in vitro studies are extended into transgenic animals using tissue specific overexpression of PTG and inducible PTG knockout lines. A second major project examines alterations in insulin sensitivity in primary human adipocyte biopsies. Two protocols are currently being used/established: disruption of sleep quality in healthy, young human subjects, and treatment of obstructive sleep apnea in women with polycystic ovary syndrome. In both studies, patients undergo complete metabolic analysis before and after intervention, while insulin action in human adipocytes isolated by needle biopsy is determined in parallel. The final project examines the role of localized glucocorticoid activation by the enzyme 11?-HSD1 in the development of obesity and insulin resistance. We are examining the effects of modulating 11?-HSD1 levels and activity on the induction of insulin resistance by glucocorticoids. These studies are currently being performed in 3T3-L1 adipocyte cell line but will be extended into primary mouse and human adipocytes. Thus, we are interested in the insulin-mediated regulation of energy storage in adipose tissue, the interplay between glucose and lipid metabolism, and the molecular mechanisms underlying the development of insulin resistance.
Ronald Cohen, M.D.
Dr. Cohen is investigating the role of corepressors in the adipocyte and other important endocrine tissues. Nuclear receptors such as the thyroid hormone receptor (TR), retinoic acid receptor (RAR), and peroxisome proliferator-activated receptor gamma (PPARgamma) have the capacity to recruit corepressors in the absence of their respective ligands or in the presence of antagonists. These corepressors, such as SMRT and NCoR, in turn form a complex with histone deacetylase activity in order to decrease gene transcription. Dr, Cohen investigates the mechanisms underlying the specificity of corepressors to distinct nuclear receptor complexes, and has shown that SMRT and NCoR repress the program of adipocyte differentiation. Studies are ongoing to dissect the roles of SMRT and NCoR in mature adipocyte function as well as in adipogenesis.
Dianne Deplewski, M.D.
Dr. Deplewski is studying the biologic and molecular basis of the growth of the sebaceous gland, using the rat preputial gland as a model. She has examined the effects of retinoic acid analogs and androgens on the growth of preputial cells in culture and the effect of the stromal-epithelial interface on the growth and ultrastructure of sebaceous cells in monolayer and lifted-raft culture. She examined the expression of 5alpha-reductase in sebaceous cells the peroxisomal proliferator activated receptors in sebaceous cells, which is a focus of the grant in which she is a co-investigator.
Her future plans are to further her studies on the role of GH and IGFs in preputial cell growth and development. Specifically, she will attempt to delineate the direct, and indirect effect of GH in the sebaceous gland system by utilizing antibodies against IGFs, and by measuring the levels of the IGFs and IGF binding proteins in conditioned media.
David A. Ehrmann, M.D.
Dr. Ehrmann has developed a clinical research program to study the genetic and physiological basis of defects in insulin secretion in women with polycystic ovary syndrome (PCOS). This is funded by a K08 award from the NIH. Dr. Ehrmann first demonstrated that women with PCOS have a characteristic supranormal elevation of 17-hydroxyprogesterone secretion in response to the endogenous gonadotropin secretion induced by administration of the gonadotropin releasing hormone agonist, nafarelin. He then showed that compaired to weight-matched controls, women with PCOS had ß-cell dysfunction which resembled that of Type 2 diabetes rather than that of simple obesity. Furthermore, his studies showed that women with PCOS who had a first-degree relative with diabetes were significantly more likely to demonstrate alterations in ß-cell function when compared to a matched group of PCOS subjects without a such family history.
The modulation by insulin of 17-hydroxylase and 17,20-lyase activities of the ovarian steroid-forming P450c17 suggests a causal link between hyperinsulinemia and the characteristic features of PCOS. Treatment with troglitazone improved not only the sensitivity to insulin but also reduced significantly the levels of total and free testosterone and the leuprolide-stimulated levels of 17-hydroxyprogesterone, androstenedione and total testosterone.
To examine the genetic basis for defects in insulin secretion and insulin action in PCOS, Dr. Ehrmann has obtained phenotypic data and DNA samples from over 240 families, totaling more than 650 individuals. This database will serve as the key resource for future studies which will focus primarily upon examining defects in pancreatic ß-cell function and genotyping candidate genes implicated in Type 2 diabetes.
Murray Favus, M.D.
Dr. Favus’ work centers on the metabolic basis of genetic idiopathic hypercalciuria in calcium oxalate stone formation, in the action of parathyroid hormone and in osteoporosis.
In the area of calcium metabolism, he has identified increases in intestinal and bone vitamin D receptor content in genetic hypercalciuric kidney stone forming rats, an animal model of human idiopathic hypercalciuria. This description represents one of the first examples of a disorder (hypercalciuria and stone formation) caused by a pathologic excess of a steroid hormone. In other studies, Dr. Favus has defined the protein kinase C signaling pathway in rat renal proximal tubules as mediating parathyroid hormone stimulation of the 25-hydroxyvitamin D-1-hydroxylase, a key regulatory enzyme in the vitamin D activation pathway. By this work he was able to assign a pathway to one of parathyroid hormone’s many biologic actions. In clinical studies, Dr. Favus participated in the multi-center trial that found the bisphosphonate alendronate sodium to be effective in the treatment of postmenopausal osteoporosis and he continues to conduct clinical studies that aim to characterize novel approaches to the treatment of osteoporosis and disorders of calcium metabolism.
Manami Hara, D.D.S., Ph.D.
Dr. Hara has generated novel mouse models for studying pancreatic beta-cell development and regeneration and islet formation. The application of sophisticated imaging techniques combined with these mouse models provides an integrated view of beta-cell proliferation and islet formation, which may have important implications for beta-cell regeneration in the adult.
Rebecca Lipton, Ph.D., M.P.H., B.S.N.
The overall goal of Dr. Lipton’s research is to understand the epidemiology, etiology and social implications of childhood diabetes, with particular reference to minority youth. Currently, her major project is a population-based incidence registry of diabetes in children ages 0-17. This study has led to clinical research in distinguishing early-onset Type 2 from more typical Type 1 diabetes as it occurs in children, as well as studies to determine correlates of early diabetes complications. The investigation of the role of genes in the etiology of autoimmune diseases of children, the determinants of health services utilization, diabetes-related mortality, and the family impact of pediatric chronic disease are major outgrowths of this research.
Plamen D. Penev, M.D., Ph.D.
Dr. Penev conducts human research studies designed to test the hypothesis that the loss of adequate sleep has an adverse effect on key metabolic and behavioral risk factors for type 2 diabetes in genetically susceptible individuals. The chance of developing type 2 diabetes in this population is markedly increased in the setting of sedentary living and excessive weight gain. Lifestyle modification combining weight loss and regular physical activity can significantly reduce the incidence of type 2 diabetes in such high-risk individuals. Therefore, the identification of modifiable factors that can interfere with or promote weight maintenance and regular physical activity may facilitate the development of improved strategies for the prevention of type 2 diabetes.
The previous studies of Dr. Penev’s group indicate that people who gain weight from overeating and physical inactivity may develop more pronounced abnormalities of glucose metabolism in the presence of recurrent sleep loss. Other findings in the laboratory suggest that the curtailment of human sleep may also interfere with the salutary metabolic effects of diet-induced weight loss in overweight individuals.
The ongoing research studies of Dr. Penev aim to integrate information about the effects of inadequate sleep on key metabolic, endocrine, cardiovascular, polysomnographic and neurobehavioral variables, such as aerobic fitness, habitual physical activity, lean body mass, degree and distribution of body adiposity, beta cell function, and insulin action in muscle, liver and fat tissue of individuals with increased risk of type 2 diabetes. These studies employ behavioral and pharmacological interventions designed to modify the 24-hour pattern of human sleep and wakefulness in inpatient or free-living settings, and involve the use of advanced in-vivo characterization of human fuel metabolism, including hyperinsulinemic and hyperglycemic clamps with stable isotopes; measurements of energy metabolism and physical activity using indirect calorimetry, doubly labeled water, and accelerometry; cardiopulmonary exercise testing; assessments of body composition and adiposity by DXA and MRI; and repeated sampling of peripheral metabolic and glucose counter-regulatory hormones.
Louis H. Philipson, M.D., Ph.D.
Dr. Philipson has focused his studies on how specific ion channels regulate intracellular calcium concentration and thereby insulin secretion in pancreatic ß-cells in normal and diabetic states. After identifying full length voltage-dependent K+ channels from a human insulinoma, he has studied this family of channels using molecular and biophysical techniques.
More recently, Dr. Philipson has produced a transgenic K+ channel mouse with ß-cell specific K+ channel expression inhibited by dominant-negative approaches. One of these expresses a green fluorescent protein- K+ channel fusion protein under the direction of the rat insulin promoter. From these studies and those utilizing stable transfected insulinoma cells expressing dominant-negative K+ channels it can be concluded that these channels exert a profound effect on intracellular calcium and are an interesting target for approaches to modulate hormone secretion.
Dr. Philipson's laboratory has cloned a channel (trp4) from ßTC3 insulinoma cells that is activated by depletion of Ca2+ from intracellular stores and 1,4,5-inositol trisphosphate. This channel is expressed in mouse and human ß-cells as well as in brain and other endocrine tissues. The mechanisms of beta cell dysfunction in homozygous or heterozygous glucokinase, HNF-1alpha, HNF-4alpha and PDX-1 mutant mice are being studied.
Samuel Refetoff, M.D.
Dr. Refetoff is Director of the Endocrinology Laboratory and the Principal investigator of a Training Program in Endocrinology and Metabolic Diseases supported by the National Institutes of Health. The contributions made by Dr. Refetoff and his group to our understanding of thyroid hormone action exemplify the strength of combining careful clinical observation and characterization with state-of- the-art in vitro systems utilizing modern approaches of cellular and molecular biology.
When Dr. Refetoff first described the syndrome of resistance to thyroid hormone (RTH) in 1967, patients with this disorder were characterized from a clinical standpoint but the molecular nature of the defects remained speculative until 1989, when his group identified the first thyroid hormone receptor beta gene mutation causing RTH. Using material obtained from more than 100 families with dominantly inherited RTH, Dr. Refetoff together with Dr. Roy E. Weiss, Chief of the Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, have explored the molecular mechanisms by which different forms of the mutant thyroid hormone receptor alter the function of the normal receptor. They established a world-wide registry for RTH containing clinical and laboratory information on about 300 families with this syndrome. Subsequently, Drs. Weiss and Refetoff identified RTH in humans without thyroid hormone receptor gene mutations and in animals deficient in the nuclear coactivator-1. Their current studies utilize animal models of RTH including thyroid hormone receptor knock outs and animals with adenovirus mediated transfer of mutant receptors.
Dr. Refetoff also discovered the syndrome of resistance to TSH and demonstrated that it is caused by loss-of-function mutations in the TSH receptor gene. He has identified mutations in the thyroxine binding globulin, transthyretin and albumin genes which result in abnormalities of thyroid hormone transport, as well as defects in the peroxidase gene that cause congenital hypothyroidism. More recently, his laboratory identified two syndromic thyroid defects combining neuropsychological and thyroid abnormalities caused by mutations in the transcription factor, TTF1 (2002) and the thyroid hormone transporter, MCT8 (2004) genes. In 2005 his laboratory identified a defect of TH metabolism caused by mutations in the SBP2 gene, which is involved in the synthesis of selenoproteins.
The combination of clinical and basic investigations of inherited syndromes of thyroid disorders serves as an ideal training ground for young physician scientists.
Robert Rosenfield, M.D.
An expert in disorders of puberty and hyperandrogenic states, Dr Rosenfield has maintained a clinically oriented research program supported by laboratory investigation. He has described the use of the GnRH agonist, nafarelin, to distinguish between ovarian and adrenal sources of androgen, to diagnose ovarian enzymatic defects in women with hyperandrogenism and to differentiate between gonadotropin deficiency and constitutional delay of puberty during the teenage years. The intermittent administration of the GnRH agonist, leuprolide acetate, is being tested in the treatment of adult men and women with gonadotropin deficiency. The transdermal administration of low dose estradiol is being used to potentiate the effect of growth hormone treatment in patients with Turner syndrome.
Dr. Rosenfield developed a system of culturing sebocytes in monolayers by activating the peroxisome proliferator activated receptors (PPARs) in rat preputial cells placed in a chemically defined, serum free medium. Definition of the factors that regulate sebocyte growth and differentiation have important implications for the development of new therapies for acne vulgaris. His long interest in the polycystic ovary syndrome (PCOS) has lead his laboratory to search for the expression of enzymes in the 17-hydroxylase and delta 4-17,20-lyase pathways that have the potential of generating androgens in the human ovary. Dr Qin, a trainee in Rosenfield's laboratory under this program, has recently shown that 17 ß-hydroxysteroid dehydrogenase 5 is expressed in human ovary. The potential role of this enzyme in the hyperandrogenic state of PCOS is being actively explored.
Donald Steiner, M.D.
The seminal discovery by Dr. Steiner that insulin is formed via a single chain precursor proinsulin, that undergoes post-translational modification, serves as a model of peptide hormone synthesis and is the basis of ongoing research in this area. More recently, the primary focus of his laboratory has been the major neuroendocrine prohormone convertases PC2 (SPC2) and PC1/PC3 (SPC3), their biosynthesis, maturation and actions on prohormone processing. For these studies he is using mice with targeted disruptions in their genes and mutational analysis of the structure and functional significance of conserved subdomains in these convertases. Additional studies involve the mechanisms of processing of insulin-like growth factor precursors and the effect of the furin gene on proinsulin processing and islet morphogenesis.
Other interests are insulin receptor structure biosynthesis, maturation through chaperone interaction, and intracellular transport. He is probing the evolution of insulin and the IGFs and their receptor proteins in lower vertebrates, with emphasis on the divergence of ligand binding, metabolic and growth regulatory functions from a single ancestral insulin-like peptide and its receptor in protochordates.
Eve Van Cauter, Ph.D.
Dr. Van Cauter is an internationally known investigator in sleep and circadian biology and their relationship with the endocrine system and glucose metabolism in normal and pathological conditions. She is also an expert in the mathematical and statistical analysis of the temporal patterns of hormonal secretion.
Dr. Van Cauter is the Principal Investigator of a Program Project which is focused on the age related changes in sleep and circadian rhythms and their implications for age-related chronic conditions. Particularly interesting from a physiologic and therapeutic standpoint are studies which aim to investigate whether replacement of growth hormone in early sleep or restoration of elevated nocturnal melatonin levels, two hormonal events which are thought to act as internal synchronizers in young adults, may correct circadian rhythm alterations in older subjects. Dr. Van Cauter has also determined the utility of the use of hormonal rhythms as markers of the human circadian clock in basic studies examining the mechanisms of entrainment of hormonal rhythms, and their implication for adaptation to jet lag and shift work. In addition, Dr. Van Cauter is one of five preceptors in the Northwestern University-University of Chicago NIH training grant for Sleep Research.
In recent years, she has led a major research program evaluating the impact of decreased sleep duration and quality on the risks of obesity and diabetes and the possible endocrine and metabolic benefits of improved sleep quality in older adults
Tamara Vokes, M.D.
Dr. Vokes has clinical practice in osteoporosis and other metabolic bone disease. Patients are referred from within the institution as well for Chicago metropolitan area and the Midwest. As a result, the fellows rotating through this clinic are exposed to wide range of bone related pathology.
Dr. Vokes’ research interest is also in the area of osteoporosis with two broad themes. The first is an investigation of clinical application of a new method for non-invasive assessment of bone structure using Radiographic Texture Analysis of bone images. The second is a study of individual and racial difference in vulnerability to glucocorticoid induced osteoporosis.
Roy Weiss, M.D., Ph.D.
Dr. Weiss is Director of the Clinical Research Center and Director of the Core laboratory. His research centers on the mechanisms of thyroid hormone action at the molecular, physiological and psychological levels. Dr. Weiss has examined the relationship between childhood Attention Deficit Disorder (ADD) and resistance to thyroid hormone (RTH). While previous studies have suggested a high incidence of ADD in patients with resistance to thyroid hormone (RTH) his prospective study of 277 children with ADD showed no instance of RTH although a 5.4% incidence of thyroid disorders was seen (normal in this age population < 1%). Hyperactivity appears to be improved in some patients with RTH and ADD who are treated with thyroid hormone but not in patients with ADD alone.
In other studies, Drs. Weiss and Refetoff have identified new mutations in the ß isoform of the thyroid hormone receptor and variable clinical and biochemical manifestations of RTH in different families harboring the same receptor mutation, suggesting that co-modulatory factors determine the phenotype in this syndrome. In separate studies, Dr. Weiss studied a large Amish kindred with familial dysalbuminemic hyperthyroxinemia (FDH) and identified a mutation in the albumin gene with increased affinity for thyroxine. More recently, Dr. Weiss has been involved in the study of mice deficient in the thyroid hormone receptor isoforms and related cofactors. He has developed a clinical research program to study pituitary tumors and in particular Cushing's syndrome.
Faculty Outside of Endocrinology that Participate in the Training Program
Eugene B. Chang, M.D.
Dr. Chang has been interested in the study of intestinal physiology and pathobiology. The studies of intestinal physiology fall into two areas: (1) investigations of host-microbial interactions of the GI tract as it relates to diet, maintenance of intestinal homeostasis, and regulation of host responses to stress and pathogens; (2) investigations of the role and regulation of intestinal epithelial transporters of nutrients and electrolytes, particularly membrane trafficking involved in controlling Na and Cl absorption. Dr. Chang’s studies of intestinal pathobiology largely focus on human inflammatory bowel diseases (IBD) and animal models of experimental colitis. A major focus has been the study of the role and function of intestinal heat shock proteins (Hsp) that are essential for maintenance of intestinal homeostasis and critically dependent on cues received from colonic microbes. In IBD and experimental colitis, Hsp expression is paradoxically down-regulated, rendering the mucosa more susceptible to injury and malignant transformation. Other studies address the role of the enteric microbiota in development of IBD and other digestive disorders. These studies incorporate the most advance technologies, including mass parallel sequencing, gnotobiotic animals, laser capture microdissection, and functional metagenomics. Approaches are being developed to better understand host responses to perturbations in colonic microbial composition and structure. These studies will provide insights into how diet and other means can be used to favorably alter host-microbial interactions of the gut, thereby preventing or treating a wide variety of diseases and maintaining good health.
Nancy Cox, Ph.D.
Dr. Cox is a human geneticist studying common disorders with complex patterns of transmission. She collaborates with other investigators in studies on type 1 and type 2 diabetes, diabetic complications, polycystic ovary syndrome, inherited thyroid defects, asthma, stuttering, specific language impairment, autism, attention deficit/hyperactivity disorder, bipolar disorder, and Tourette Syndrome. Her role on these projects includes participation in study design and data management, as well as primary responsibility for genetic analyses, including linkage analysis and the follow-up genetic analyses conducted in the context of positional cloning studies, as well as genome-wide association studies.
Populations studied include out bred U.S. Caucasian populations, as well as Japanese and Chinese Asian populations and admixed population including African-American and Mexican-American populations and an inbred isolated population of Hutterites. Because of challenges that have arisen during the course of analyses on these data, Dr. Cox has developed a research program in the development and extension of methods for genetic analysis, including both linkage analysis and genome-wide association studies.
Marshall H. Chin, M.D., M.P.H.
Dr. Chin is the Director of the DRTC Prevention and Control Core, Associate Director of the Robert Wood Johnson Clinical Scholars Program. He and his colleagues from a consortium of 70 community health centers in the Midwest are currently funded by the Agency for Healthcare Research and Quality (AHRQ) and Robert Wood Johnson Foundation to improve the quality of diabetes care in health centers that serve the indigent. This multifactorial, community-based intervention includes rapid quality improvement, chronic disease management, provider training in behavioral change, and patient empowerment interventions. Dr. Chin also focuses on geriatric diabetes issues to assess the treatment preferences of older patients with diabetes.
Godfrey Getz, M.D., Ph.D.
Dr. Getz' group is studying the role of apolipoproteins E and A-I in atherosclerosis and Alzheimer’s disease by structure function analysis in cell culture and genetically modified mice. The removal of the apoE gene in mice results in profound hyperlipoproteinemia causing severe atherosclerosis that closely resembles that seen in man. Mice doubly deficient in apoE and the recombination activation gene (RAG2) have reduced plasma cholesterol and triglyceride levels and less atherosclerosis in some vascular sites. Similarly mice deficient in both LDL receptor and RAG2 have less hyperlipoproteimia and less atherosclerosis. Dr. Getz is using these models to explore the effects of the immune system on both plasma lipoproteins and atherosclerosis, by adoptive transfer experiments and cytokine administration.
Dr. Getz's laboratory has demonstrated that ? amyloid, the protein that accumulates in the brain of Alzheimer’s patients, forms a stable complex with apoE2 and E3 and not E4, perhaps facilitating the clearance of the ? amyloid. They are now studying the effect of apo E containing lipoproteins on the repair of experimentally injured mouse hippocampus, the primary focus of pathology in Alzheimer’s disease.
Somatic gene transfer is being used to express phosphoenolpyruvate carboxykinase, the major enzyme involved in hepatic gluconeogenesis and thus producing hyperglycemia and hyperinsulinism, as observed in diabetes mellitus.
Theodore Karrison, Ph.D.
Dr. Karrison is an experienced statistician whose statistical research interests include clinical trials methodology, survival analysis, and methods for analyzing multiple endpoints. Dr. Karrison presents a didactic lecture series on statistical methods on an annual basis which all trainees are encouraged to attend. In his function as statistical consultant to the GCRC, he provides a detailed critique of the proposed studies design and statistical methods. Trainees are encouraged to interact individually with Dr. Karrison to receive advice on the best approach to the statistical analysis of their own data.
Anthony Kossiakoff, Ph.D.
Dr. Kossiakoff’s research interests are in the areas of protein engineering and design using x-ray crystallography, mutagenesis, and peptide synthesis.
The studies in Dr. Kossiakoff’s laboratory are focused on the broad objective of understanding ligand-receptor interactions. The structures of several hormone-receptor complexes will be solved to provide the structural basis for resolving the role of conformational versatility in determining the binding and specificity of these molecules. The work will also include a set of integrated phage display mutagenesis studies to dissect the cooperativity effects and energy contributions of the residues forming the binding interfaces.
The experimental approach combines X-ray crystallography and biophysical analyses with the power of phage display mutagenesis. The feasibility of each research area is established through preliminary studies. The primary structure data will be obtained by solving prolactin and variant growth hormone receptor complexes. Crystals and data for two systems have been obtained. As a long-range goal, to assess the capabilities of conformational versatility, structural analyses will be used and the extensive molecular diversity available from phage display to explore the stereochemical limits for binding solutions available to growth hormone-like molecules to the growth hormone receptor.
Ronald A. Thisted, Ph.D.
Dr. Thisted, a biostatistician/epidemiologist, is studying regression methods for paired data with ordered categorical outcomes, problems of multiple inference in clinical trials, methods for combining information (meta-analysis) concerning diagnostic tests such as those used in nuclear medicine, and assessment of causal relationships associated with rare but catastrophic events such as sudden death in children. He will be responsible for aspects of the training related to biostatistics and data analysis.