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Goals Goals: The primary goal of the Pediatric Endocrinology training program is to train pediatricians for careers in academic and investigate endocrinology and metabolism. To this end, the program provides extensive clinical training as well as a multi-disciplinary environment for biomedical research applicable to studies of endocrinology and metabolism. Eligibility: Physicians appointed to the training program will have completed at least three (3) years of clinical training and be board-certified or eligible in Pediatrics. Because of the 2nd and 3rd years of our training program are often funded by the National Institutes of Health. Fellows must be U.S. citizens or permanent residents. In general, two fellows are accepted yearly. Application: There is no formal application. A curriculum vitae with names of reference is sufficient; these items can be sent to perrin.white@utsouthwestern.edu. Reference letters should be sent only upon request of the Program Director. There is no formal application deadline, but we generally accept fellows more than one year in advance. An initial interview is conducted by telephone; if there is sufficient mutual interest, a visit to Dallas is arranged. Environment: The University of Texas Southwestern Medical Center at Dallas is located on 60 acres and consists of 21 major buildings with 2.2 million square fee of offices, laboratories, and support space. In addition to the above space there are four (4) major hospitals in the complex: Parkland Memorial Hospital, Zale Lipshy University Hospital, Children's Medical Center and St. Paul Hospital. An additional 30 acre site ("the north campus") is connected by an overhead transport system requiring a three (3) minute transit. The north campus has its first three (3) research buildings open and the 4th is under construction. A total of two (2) million square feet of new research space will be built over the next decade. The inpatient services at Children's Medical Center consist of approximately 320 beds most of which are in private rooms with an additional 50-60 bassinets in the Intensive Care Nursery at Parkland Hospital. The emergency room and pediatric intensive care unit rank among the busiest in the nation. Additional information can be obtained from the web sites: www.peds.swmed.edu and www.childrens.com. Organization: In general, the training program in Pediatric Endocrinology includes one year of clinical training and two (2) years of training in investigative endocrinology/metabolism. The clinical training year consists of twelve (12) months devoted to acquiring skills in the diagnosis and management of clinical problems, divided equally between inpatient and outpatient rotations. Trainees in the 2nd-3rd years of the program are expected to spend approximately 1/2 to one day a week in outpatient activities to maintain clinical skills. During this period of time, however, they will not participate in management of the inpatient services and thus will devote at least 80% of their time to research activities. Trainees take night and weekend call every fourth week in the first year and an average of every eighth week in subsequent years. Clinical Staffing: Current clinical activities are supported by seven (7) attending physicians, two (2) nurse practitioners, five (5) additional diabetes nurse-educators, five (5) endocrine nurses, four (4) medical assistants, a nutritionist, and a social worker. Conferences and Didactic Instruction: Fellows usually attend Pediatric or Endocrine Grand Rounds weekly, as well as, laboratory meetings during their second and third years. Pediatric fellows have a weekly conference with Dr. White, which serves as tutorial, journal club, and research in progress discussion. Both Pediatric and Adult endocrine fellows also attend a weekly Fellows' Conference organized by the trainees with the assistance of Dr. Richard Auchus. The purpose of this conference is for trainees to discuss informally their research projects, emphasizing experimental design and interpretation of data. This forum provides an opportunity for each trainee to become familiar with the research projects of others. Formal coursework from the various graduate programs at UT Southwestern is not required but is available depending on the interests and background of each fellow. Examples of relevant courses might include:
Except under unusual circumstances, a trainee will not participate in more than one graduate course per semester. All fellows are strongly encouraged to attend the annual symposium organized by the Center for Training in Clinical Investigation on "Techniques of Patient-Oriented Research". Topics covered in this one-day symposium include medical ethics, conflicts of interests, protection of human subjects and protocol preparation, designing clinical research, grantsmanship, and the role of the GCRC in clinical research. Finally, we particularly are excited by the recent establishment of a School of Public Health at UT Southwestern Medical Center. Several important research topics (e.g. biostatistics, epidemiology, and outcome-mediated clinical research) will fall within the purview of the School of Public Health, and we anticipate that these evolving programs will serve as a positive impetus to facilitate instruction of our trainees in these key aspects of clinical research. Training Program and Faculty: The research interests of all Pediatric Endocrinology faculty members are described elsewhere on this website. The faculty of the NIH-supported Endocrinology Training program consists of 19 faculty members from the Department of Internal Medicine (11), Pediatrics (1), Molecular Genetics (1), Biochemistry (1), Pharmacology (2), Obstetrics-Gynecology (2) and the McDermott Center for Human Development (1). Several members of clinical departments also hold joint appointments in basic science departments [e.g. Biochemistry (1), Pharmacology (2)]. Most of these preceptors have well-established track records for training young biomedical researchers who assume independent positions in biomedical research. Some of the younger faculty mentors are still establishing a record of success in this regard; as noted above, the strengths of their research programs justify their inclusion among the Program Faculty. One member of the training faculty will also serve as Advisor for each of the trainees, such that each fellow will have a source of direction independent of the mentor to ensure that timely progress is being made and that the needs of the trainee are met. Additional faculty members in the Departments of Internal Medicine, Pediatrics, and Obstetrics-Gynecology, although not included among program faculty, contribute to the clinical instruction of trainees and serve as collaborators and sources of patient referral for clinical research projects. Moreover, they attend many of the research seminars and clinical conferences, providing balance and experience for these discussions. Historically, there has been a strong emphasis on collaborative research at UT Southwestern. Most recently, such activity has been encouraged and fostered by the chairmen of the clinical and basic science departments. The existence of an Endocrinology and Metabolism Training Program has facilitated interactions among investigators with common interests, as shown by long-term evidence of co-authored publications (cf. Parker/Hobbs, Parker/White, Parker/Mangelsdorf, Parker/Rainey, Parker/Dobbins, Rainey/White, Russell/White, McPhaul/Russell, Hammes/Auchus) that reflect both the congruent research interests of preceptors and synergistic interactions between preceptors applying different methodologies to endocrine research. These interactions have given rise to several common themes of research that are pursued by investigative teams from multiple laboratories or within a single laboratory. A discussion of these themes and the faculty within each is provided below. Because of their multiple research interests, some faculty members are listed under more than one theme. Mechanisms of Steroid Hormone Biosynthesis Richard J. Auchus, M.D., Ph.D., Stephen Hammes, M.D., Ph.D., Michael J. McPhaul, M.D., Carole R. Mendelson, Ph.D., Keith L. Parker, M.D., Ph.D William E. Rainey, Ph.D., David W. Russell, Ph.D., Perrin C. White, M.D A traditional focus at UT Southwestern has been defining the mechanisms of steroid hormone biosynthesis, which continues as a common theme for a number of faculty members within the Training Program, resulting in a critical mass of laboratories applying state-of-the-art approaches to key questions in this area. The Auchus laboratory studies the two principal classes of enzymes in steroid biosynthesis, cytochromes P450 and hydroxysteroid dehydrogenases. They seek to elucidate the biochemical basis for the physiological functions of these enzymes, including the structural basis for regioselective hydroxylations by CYP17 and CYP21, the mechanism of action of cytochrome b5 on 17, 20-lyase activity, and the mechanisms that dictate directional preferences of hydroxysteroid dehydrogenases. A separate line of investigations explores the genetics of 17-hydroxylase deficiency, isolated 17, 20-lyase deficiency, and 17-hydroxysteroid dehydrogenase type 3 deficiency, including manifestations in heterozygotes. The Auchus laboratory collaborates with a number of other laboratories in the Endocrinology and Metabolism Training Grant in projects that include: define the biosynthetic pathways and biologically active products that mediate the maturation of xenopus oocytes (Hammes), elucidating the biochemistry of lipodystrophy syndromes (Garg), and exploring the pathways of metabolism of testosterone and dihydrotestosterone in mice (McPhaul). The Hammes laboratory studies the role of steroidogenesis in regulating meiosis in the ovary. In collaboration with the Auchus laboratory, they have demonstrated that, in Xenopus laevis, ovarian expression of the enzyme CYP17 is exclusively in oocytes, while surrounding follicular cells contain all other enzymes necessary for steroidogenesis. They further have shown that CYP17 activity is crucial for normal oocyte meiosis, suggesting an unusual model whereby germ cells play an important role in regulating their own maturation. The Hammes and Auchus labs are continuing to characterize Xenopus CYP17, as it is the most potent isoform of CYP17 described, and may serve as a useful model for studying this complex enzyme. A major focus of the Mendelson laboratory is defining the molecular mechanisms involved in tissue-specific and hormonal regulation of aromatase expression. The human CYP19 gene is selectively expressed in a number of tissues, including ovarian granulosa and luteal cells, adipose stromal cells, syncytiotrophoblast of the placenta, and discrete regions of the brain. Aromatase expression in these tissues is regulated by the use of different tissue-specific promoters, which lie upstream of unique first exons encoding 5’-untranslated regions of the aromatase mRNAs. A collaborative study with the Parker laboratory studies the roles of orphan nuclear receptors in aromatase expression by granulosa cells. The laboratory recently identified a 250 bp region, which lies ~100,000 bp upstream of the CYP19 translation initiation site and directs placenta-specific expression in transgenic mice. Studies in the Parker laboratory seek to define the mechanisms that control the development of the adrenal glands, ovaries, and testes. One focus is the orphan nuclear receptor steroidogenic factor 1 (SF-1), initially identified as a global regulator of the cytochrome P450 steroid hydroxylases that make steroid hormones. Gene knockout studies showed that SF-1 knockout mice lacked adrenal glands and gonads, had impaired function of pituitary gonadotropes, and lacked one region of the hypothalamus, the ventromedial hypothalamic nucleus. Ongoing studies will use tissue-specific gene knockouts to define the precise roles that SF-1 plays at different levels of the endocrine axis. A related goal is to identify the SF-1 target genes whose expression is essential for adrenal and gonadal development. Defining the mechanisms controlling zonation of the adrenal cortex is the goal of the Rainey laboratory. The research focuses on the regulation of adrenal expression of angiotensin II receptor and steroidogenic enzymes that exhibit zone-specific localization. Aldosterone synthase (CYP11B2) and angiotensin II receptors in the glomerulosa play pivotal roles to maintain aldosterone production. In contrast, cells of the zona fasciculata express 17α-hydroxylase (CYP17) and 11ß-hydroxylase (CYP11B1), which are necessary for glucocorticoid synthesis. The Rainey laboratory is determining the signal transduction systems and transcription factors that mediate zone-specific expression of these enzymes and angiotensin II receptors. In collaboration with Dr. White, they further are analyzing the CYP11B2 promoter to identify transcription factors influencing its expression. Knowledge of the mechanisms leading to adrenal zonation should increase our understanding of diseases that result from alterations in the profile of steroids produced within the adrenal cortex. Work in the Russell laboratory spans two areas of biology: the biosynthesis and physiological roles of androgens and pathways of cholesterol/ oxysterol metabolism. With respect to androgen action, the conversion of testosterone into dihydrotestosterone by steroid 5α-reductase is a key reaction that is essential both for male sexual differentiation during embryogenesis and for postnatal growth of androgen-dependent tissues such as the prostate. As defined initially by the Russell laboratory, two distinct 5α-reductase isozymes have been identified. Deficiencies in these isozymes lead to male pseudohermaphroditism in humans or impaired parturition in female mice, and the roles of these enzymes in normal reproductive functions are an area of active investigation in the laboratory. The White laboratory uses molecular genetic approaches to study human diseases, concentrating on inherited disorders of steroid biosynthesis and metabolism. Past work included studies of congenital adrenal hyperplasia, disorders of aldosterone biosynthesis and inherited forms of hypertension. At present, the White laboratory is studying mechanisms regulating activity of the two isozymes of 11ß-hydroxysteroid dehydrogenase (11-HSD1 and 11-HSD2). These isozymes convert active cortisol and inactive cortisone, thus modulating local concentrations of glucocorticoids in a tissue-specific manner. Previous work by the laboratory has demonstrated that defects in 11-HSD2 cause a genetic form of high blood pressure, apparent mineralocorticoid excess. In collaborative work, the laboratory has demonstrated that polymorphisms in the gene for 11-HSD1 cause cortisone reductase deficiency, which consists of overactivity of the adrenal cortex and a form of polycystic ovary syndrome, when these polymorphisms are inherited together with mutations reducing the activity of the hexose-6-phosphate dehydrogenase (H6PD) enzyme. The mutations in H6PD affect electron transport within the endoplasmic reticulum. Mechanisms underlying this phenomenon are being investigated biochemically and by developing a mutant mouse model of cortisone reductase deficiency.
The Hammes laboratory is interested in how steroid hormones interact with membranes to mediate transcription-independent, or nongenomic effects. Specifically, the laboratory studies nongenomic androgen-induced maturation of frog and mouse oocytes. Their interest in this system is three-fold: First, androgen-induced oocyte maturation is a reproducible and biologically relevant event. Second, oocytes can be manipulated with relative ease in vitro to study nongenomic steroid-mediated signaling. Third, the potential clinical importance of this system is compelling, as physiologic androgen concentrations appear to be important for ovarian development, while supra-physiologic concentrations may promote ovarian pathology such as polycystic ovarian syndrome (PCOS). The Hammes laboratory has recently discovered selective androgen receptor modulators (SARMs) that specifically promote genomic or nongenomic AR-mediated events, suggesting that it may be possible to develop targeted regulators of oocyte maturation that can be used to treat some forms of infertility. The McPhaul laboratory has explored the mechanism of action of steroid hormones by studying genetic defects that cause resistance to the action of androgens. 46, XY males with defects within the X-linked androgen receptor (AR) gene manifest a range of phenotypic abnormalities, ranging from men with mild defects in virilization to individuals who are phenotypically female. Studies by the McPhaul group have identified over 30 different specific genetic defects in the AR gene in patients with androgen resistance. Taking these patients as a point of departure, the McPhaul laboratory is using biochemical, physical, and gene targeting methods to understand how these mutations alter AR function and how such defects of AR function alter male phenotypic development. Specific projects include: 1) Identifying factors that interact with the AR to alter or mediate its function; 2) Using microarray expression profiles to identify genes that are differentially regulated differentially by testosterone and dihydrotestosterone: 3) Using similar microarray approaches to identify genes that are regulated by androgen in 15 different tissues of the mouse, thereby defining the targets of AR in individual cell types and hopefully providing a conceptual framework for understanding the mechanisms by which selective androgen receptor modulators (SARMs) exert their effects. A second line of research in the Mendelson laboratory seeks to define the mechanisms that regulate surfactant protein gene expression during lung development. Pulmonary surfactant, a developmentally-regulated lipoprotein that is synthesized by type II cells of the lung alveoli, reduces surface tension and prevents alveolar collapse. The major protein of lung surfactant is surfactant protein A (SP-A), whose expression in the fetal lung is initiated only after 75% of gestation is completed. SP-A gene expression in fetal lung in vitro is regulated by glucocorticoids and by hormones that increase the cellular levels of cyclic AMP. Studies with transgenic mice and primary cultures of type II pneomocytes in culture are being implemented to map the regions that mediate the tissue-specific, developmental and hormonal regulation of expression of SP-A. The transcription factors that bind to these regions are being isolated and characterized to define their roles in the regulation of SP-A expression. David Garbers, Ph.D., Lisa Halvorson, M.D., Keith L. Parker, M.D., Ph.D., Andrew Zinn, M.D., Ph.D. Dr. Parker has worked to strengthen interactions between Endocrinology and Metabolism and Reproductive Endocrinology (Obstetrics-Gynecology) and to increase the exposure of the fellows to aspects of reproductive biology. The genetic basis of reproductive function has long been a focus of investigators at UT Southwestern, and several laboratories explore this theme. Research in the Garbers laboratory concentrates on the molecular basis of fertilization, nuclear reprogramming (cloning), male germ cells and a family of receptors known as guanylyl cyclases. A number of new sperm membrane proteins recently have been discovered in the laboratory. Efforts are underway to clone both mice and rats and then to study the mechanism(s) of nuclear reprogramming. Seven guanylyl cyclase receptors have been cloned, three of which possess known ligands. One of the ligands is an important natural regulator of blood pressure, and one regulates intestinal fluid secretion. The function of the ligand for the other receptor remains unclear, but the receptor is expressed in high amounts in fibroblasts suggesting a possible role in tissue remodeling. Four of the cyclases remain orphan receptors and searches for their putative ligands are in progress. The Halvorson laboratory studies the mechanisms that regulate the expression of gonadotropins in the anterior pituitary. One focus of her studies is the orphan nuclear receptor SF-1, which regulates expression of the ß-subunit of luteinizing hormone by pituitary gonadotropes. In cell culture models, she has shown that GnRH induces LHß in part by inducing the expression of Egr1, a zinc finger transcription factor that interacts with steroidogenic factor 1 to regulate the LHß promoter. In collaboration with Dr. Parker , she is now using mice with a pituitary-specific knockout of SF-1 as a novel genetic model of hypogonadotropic hypogonadism. Analyses of SF-1 knockout mice by the Parker laboratory showed that SF-1 is essential for gonadal development. Gene regulation studies have linked SF-1 to the production of androgens, insulin-like peptide 3 (Insl3), and anti-Mullerian hormone, suggesting that it is essential for the production of the mediators of male sexual differentiation. Ongoing studies seek to identify target genes of SF-1 that mediate its key roles in the gonads, and to make cell-specific SF-1 KO mice that lack SF-1 specifically in Leydig cells or Sertoli cells. The Zinn laboratory studies genetic disorders of human growth and reproduction, with special focus on Turner Syndrome and female infertility. Turner syndrome, a human chromosome disorder involving the loss of one sex chromosome, affects one in two thousand to one in five thousand live born girls and is a major cause of fetal wastage during pregnancy. Principle features include short stature, infertility, anatomic abnormalities, and specific deficits in visual-spatial and certain other cognitive abilities. Dr. Zinn is collaborating with Dr. Judith Ross, a pediatric endocrinologist at Thomas Jefferson University, to map specific genes responsible for various features of Turner syndrome by characterizing subjects with partial X deletions. A related project examines the role of X-linked genes in premature ovarian failure, a condition that affects roughly 1 in every 300 women. Molecular Mechanisms of Lipid Biosynthesis and Metabolism Abhimanyu Garg, M.D., Scott Grundy, M.D., Ph.D., Helen Hobbs, M.D., David J. Mangelsdorf, Ph.D, Keith L. Parker, M.D, Ph.D., David W. Russell, Ph.D. Perhaps the preeminent research strength at UT Southwestern has been in the area of cholesterol biosynthesis and lipoprotein metabolism, as evidenced by the Nobel Prize-winning research of Drs. Brown and Goldstein. This highly successful focus on basic mechanisms of cholesterol and lipid metabolism continues at UT Southwestern, largely within the laboratories of faculty mentors from the Endocrinology and Metabolism Training Grant. In addition to its significance in the basic sciences, UT Southwestern has had a profound impact on clinical approaches to the diagnosis and management of dyslipidemic states in human patients. Indeed, the first patient whose familial hypercholesterolemia was cured by liver transplant was diagnosed and followed here at UT Southwestern. As a result, UT Southwestern continues to attract physician-researchers who are deeply committed to developing new approaches to these conditions, which are major contributors to cardiovascular morbidity and mortality. Dr. Garg has made major advances in the area of congenital lipodystrophy resulting from mutations in genes such as lamin A and 1-acyl-sn-glycerophosphate acyltransferase 2 (AGPAT2) gene. The AGPAT2 enzyme acylates lysophosphatidic acid to form phosphatidic acid, a key intermediate in the biosynthesis of triacylglycerols and glycerophospholipids. Having proved that AGPAT2 mutations can cause lipodystrophy, Dr. Garg now is determining the functional implications of mutations in the AGPAT2 gene found in patients with CGL. He also has made important contributions to our understanding of the pathogenesis of HIV-related lipodystrophy. From a therapeutic standpoint, his collaborative studies showing a beneficial effect of leptin therapy in patients with generalized congenital lipodystrophy are a landmark for treating patients with these rare but fascinating metabolic disorders. Dr. Grundy, the Director of the Center for Human Nutrition, investigates the metabolic and genetic basis of atherogenic dyslipidemias, including the syndromes of isolated low levels of HDL and elevated levels of serum triglycerides. These investigations include identifying major genes for the various forms of dyslipidemia by family linkage studies, identifying polymorphisms in candidate genes linked to dyslipidemic traits, and demonstrating functional significance of these polymorphisms through association studies and metabolic research. Linkage studies have identified the hepatic lipase gene as a powerful determinant of HDL levels, and new polymorphisms that affect the functional activity of hepatic lipase have been identified. A similar approach is being taken to the study of the genetic basis of primary hypertriglyceridemia. Finally, metabolic studies on the role of insulin resistance and unesterified fatty acids in the development of primary hypertriglyceridemia are being performed. Over the last fifteen years, the Hobbs laboratory has sought to identify genes that contribute to inter-individual variations in levels of two atherogenic lipoproteins: low density lipoprotein (LDL) and lipoprotein (a) [Lp(a)]. To identify genetic factors that lead to variations in lipoproteins levels, Dr. Hobbs has characterized plasma lipoprotein levels in over 500 families in which multiple family members have elevated lipoprotein levels. They also recently identified genes encoding members of the ABC transporter family that play critical roles in limiting the amount of dietary cholesterol that accumulates in the body. In a related project, Dr. Hobbs is investigating why some individuals are predisposed to develop high plasma cholesterol levels on a high cholesterol diet. Levels of Lp(a)—a risk factor for developing heart disease —differ considerably between individuals and ethnic groups. The The Mangelsdorf laboratory studies the LXR family of nuclear receptors. Through a comprehensive screen of lipid extracts from LXR-expressing tisseus, specific oxysterols were shown to activate the LXRs. These oxysterols, which derive from cholesterol, serve as important intermediates in several rate-limiting biochemical pathways, including steroid hormone and bile acid synthesis. Consistent with this model, knockout mice and differential display analyses suggest that LXRs (and their oxysterol ligands) act as cholesterol sensors to regulate crucial metabolic pathways that determine the catabolism of cholesterol. Another focus of the Parker laboratory is a protein that is important for cholesterol trafficking within the cell, the steroidogenic acute regulatory protein (StAR). To facilitate analyses of its function in vivo, StAR knockout mice were developed. These mice, which are unable to translocate cholesterol to the mitochondria, have severe defects in the production of all steroids. This mouse model of a human genetic disease is being used to gain new insights into the roles of StAR within steroidogenic cells in an intact endocrine milieu. In addition to their work on androgen biosynthesis, the Russell laboratory also studies the enzymes and genes that oxidize cholesterol to bile acids and oxysterols. Bile acids—which are essential for life--are made in the liver and secreted into the gut to facilitate the absorption of dietary cholesterol, fats, and fat-soluble vitamins. Over a dozen enzymes located within distinct subcellular compartments of hepatocytes mediate their synthesis. The Russell laboratory has used biochemical, molecular biological, and genetic approaches to isolate genes that participate in this pathway; ongoing studies will use physiological studies and targeted gene disruption to determine the roles of these genes in cholesterol metabolism. Mechanisms and Treatment of Diabetes Mellitus Philip Raskin, M.D. Intermediary metabolism and insulin action have long been areas of considerable strength at UT Southwestern. Indeed, this area has been the focus of investigation by the previous program director, Dr. Daniel Foster, and continues to attract intense interest among program faculty. New lines of investigation are using the power of genetics and transgenesis to develop new model systems relevant to the pathogenesis and therapy of diabetes mellitus. In addition, more clinically oriented studies of diabetes mellitus provide a unique forum for instructing trainees in the application of clinical research approaches to this important disorder. Dr. Raskin occupies a unique niche for clinical research training within our Endocrinology and Metabolism Training Program. Over the past 25 years at UT Southwestern, he has served as our premier expert in diabetes mellitus and its management. He was a co-investigator in perhaps the quintessential clinical study in diabetes management—the DCCT—and recruited and followed more patients than all but one center in this landmark study. Since his participation in the DCCT, Dr. Raskin has continued his studies into the mechanisms and management of Type I and Type II diabetes mellitus. Particular areas of emphasis include: management of diabetic complications (e.g. nephropathy, retinopathy, and neuropathy) and the potential role of combination therapy in improving diabetic control. Given the enormous impact of diabetes mellitus and the morbidity and mortality of its complications throughout the world—as recognized by NIDDK initiatives directed at basic and clinical aspects of Diabetes research—these studies provide an essential training opportunity for our research fellows. In addition, the striking impact of diabetes mellitus on the Hispanic community has served as a powerful inducement for Hispanic physicians to come to UT Southwestern for further training in Endocrinology and Diabetes Research (see below for further description of our minority recruitment efforts). In recognition of his contributions to Diabetes Research and Care, he will receive the Denis McGarry Award of the American Diabetes Association in 2004. Obesity The explosive increase in obesity in developed nations and its multiple accompanying co-morbidities highlight the need for an improved understanding of the basic mechanisms of body weight regulation. Investigation of the central mechanisms of body weight regulation is a common focus for two of the laboratories. The Parker laboratory has focused on the role of the ventromedial hypothalamic nucleus in the regulation of body weight. SF-1 is expressed in the VMH, and knockout mice lacking SF-1 have marked structural abnormalities of the VMH. The laboratory is using transgenic targeting to restore expression of genes such as the leptin receptor and tubby to the VMH, hoping to achieve a correction of the obesity caused by mutations in these genes. The Zinn laboratory has characterized at a molecular level the genetic defect in a young girl with unexplained severe obesity and accelerated linear growth. The defect involves SIM-1, a transcription factor expressed in the paraventricular nucleus of the hypothalamus. Studies seek to define the relationship between SIM-1 and other hypothalamic signaling pathways implicated in obesity such as the leptin and melanocortin systems. Khashayar Sakhaee, M.D. Dr. Sakhaee and his group are interested in defining the clinical and molecular aspects of three common conditions that lead to nephrolithiasis. Absorptive hypercalciuria is due to intestinal hyperabsorption of calcium. Analyses of three large kindreds have implicated mutations in an adenylyl cyclase as potential causes of this disorder. They also have followed a large number of patients with cystinuria. In type I cystinuria, they have identified nine novel mutations in the SLC3A1 gene. However, approximately 50% of patients lack definable mutations in this gene, suggesting that other genes are also involved. Currently, family studies are underway in an attempt to define linkage for these other genes. Finally, Drs. Sakhaee has proposed a new pathogenetic scheme that implicates insulin resistance in the pathogenesis of primary gout. Their studies suggest that improving insulin resistance with troglitazone will lead to an increase in urinary pH and a concomitant increase in the fractional excretion of uric acid. Such therapeutic interventions may prove valuable in kindreds with a strong family history of stones.
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Copyright 2008. The University of Texas Southwestern Medical Center at Dallas 5323 Harry Hines Boulevard, Dallas, Texas 75390. Telephone 214-648-3111 |
