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Program in Developmental Endocrinology and Genetics
Director: Forbes D. Porter, MD, PhD
The mission of the Program on Developmental Endocrinology and Genetics (PDEGEN) is to carry out translational or transformative research in endocrine or genetic disorders. The research, basic or clinical, should be uniquely suited to the intramural research program, be of high quality, and should have a focus consistent with the mission of NICHD. The PDEGEN is also committed to providing first-class training in the conduct of basic, translational, and clinical research and to supporting a nationally recognized, accredited Pediatric Endocrine Fellowship Training Program. PDEGEN investigators have diverse expertise ranging from biochemistry to molecular endocrinology, genetics, and clinical obesity research.
Jeffrey Baron's Section on Growth and Development investigates the cellular and molecular mechanisms governing childhood growth and development. The basic research performed in this section focuses on the mechanisms that allow rapid cell proliferation and body growth in young children and that subsequently suppress proliferation, causing body growth to slow and eventually halt by adulthood. The group discovered that juvenile growth deceleration is attributable in part to a multi-organ genetic program, which involves the downregulation of a large set of growth-promoting genes. Recent studies focused on the molecular mechanisms orchestrating this program. Elucidating such growth-limiting mechanisms not only provides insight into childhood growth disorders but also has broader medical applications because disruption of these regulatory systems contributes to oncogenesis; conversely, transient therapeutic suspension of these regulatory systems in adult cells might be used to achieve tissue regeneration. For the Section’s clinical research, one major focus involves the use of high-throughput sequencing and other molecular-genetic approaches to study patients with growth disorders, including both growth failure and overgrowth.
Janice Chou's Section on Cellular Differentiation conducts research to delineate the pathophysiology of glycogen storage disease type Ia (GSD-Ia), deficient in G6Pase-alpha (or G6PC), GSD-Ib, deficient in the glucose-6-phosphate transporter (G6PT or SLC37A4), and glucose-6-phosphatase-beta (G6Pase-beta or G6PC3) deficiency, and to develop gene therapies for these disorders. Chou's group showed that G6PT, SLC37A1, and SLC37A2 are endoplasmic reticulum (ER)–associated phosphate-linked antiporters but that only G6PT matches the characteristics of the physiological ER G6P transporter. The Section also showed that neutrophils express the G6PT/G6Pase-beta complex and that inactivation of G6PT or G6Pase-beta leads to the enhanced neutrophil apoptosis that underlies the neutropenia in G6Pase-beta deficiency and in GSD-Ib. Chou's group further showed that G6Pase-beta is essential for energy homeostasis in neutrophils and macrophages. G6Pase-beta deficiency prevents recycling of ER glucose to the cytoplasm, leading to neutrophil/macrophage dysfunction. More recently, Chou's group showed that the mechanism of neutrophil dysfunction in GSD-Ib arises from activation of the HIF-1 alpha/PPAR-gamma pathway. Chou's Section developed mouse models of GSD-Ia, GSD-Ib, and G6Pase-beta deficiency. Using GSD-Ia mice, the Section developed an adeno-associated virus (AAV) vector–mediated gene transfer that corrects hepatic G6Pase-alpha deficiency and prevents chronic hepatocellular adenoma formation. The AAV vector developed by Chou's group is the leading candidate in clinical trials for the treatment of human GSD-Ia.
Angela Delaney's Unit on Genetics of Puberty and Reproduction investigates the mechanisms responsible for pubertal onset in children. In collaboration with the Reproductive Endocrine Unit (REU) at the Massachusetts General Hospital (MGH), and under the mentorship of William Crowley, one of the world's leading experts on disorders of gonadotropin-releasing hormone (GnRH) secretion, Delaney is conducting translational research on the neuroendocrine and genetic control of GnRH secretion and its regulation of gonadotropin secretion and gonadal physiology. The collaboration aims to phenotypically and genetically characterize subjects with isolated hypogonadotropic hypogonadism (IHH) and other, more common disorders of puberty. The Unit is using insights gained from the investigation of this clinically and genetically heterogeneous group of GnRH–deficient patients to explore the biological pathways that may contribute to the reactivation of GnRH secretion at puberty. In collaboration with the REU, a variety of molecular techniques are used to further characterize the known genetic defects causing IHH, as well as to identify new genes responsible for the regulation of pubertal onset. Such approaches will help define the developmental physiology of pubertal development in order to gain increased understanding of human disorders of puberty and reproduction.
Maria Dufau's Section on Molecular Endocrinology investigates the molecular basis of hormonal regulation of gonadal function, focusing on: (i) modes of transcriptional repression and derepression of receptors for human luteinizing hormone (LHR); (ii) functions of novel short prolactin receptor (PRLR) inhibitory forms, identified by the Section, in physiological regulation and cancer and the role of prolactin in transcriptional regulation/expression of PRLR in breast cancer; (iii) mechanisms involved in Leydig cell function, intracrine and paracrine androgen actions in the progression of spermatogenesis, and the regulation/functions of GRTH/DDX25, an androgen-regulated RNA helicase, essential for spermatogenesis and discovered by this group. Recent studies revealed the essential role of Positive Coactivator 4 (PC4), which associates with Sp1 at the LHR promoter, in the formation/assembly of the pre-initiation complex in LHR transcription. The Section found that histone 3 (H3) is recruited to the PC4 complex during the activation state of the receptor and that, in the complex, H3 is in an acetylated form. The sites of H3 acetylation and the impact of the PC4:acH3 complex on chromatin structure are under study. Other work demonstrated conformational determinants required for the inhibitory action of the PRLR short form (SF) on prolactin-induced signaling through the long form (LF). Studies revealing the essential role of the D1 domain of the PRLR on the SF configuration for its inhibitory action on LF–mediated function provide the basis for developing drugs of potential use in the treatment of advanced breast cancer. Also, the group provided direct evidence for local actions of prolactin independent of estradiol, with participation of the estrogen receptor in up-regulation of PRLR transcription/expression in breast cancer cells, which is of relevance to states that are refractory to therapy with aromatase inhibitors. Gonadotropin-regulated testicular helicase (GRTH/Ddx25), present in Leydig and meiotic/haploid germ cells, is a multifunctional protein that participates in nuclear transport of specific messages essential for the progress of spermatogenesis and protects Leydig cells from gonadotropin-mediated overstimulation of androgen. A transgenic animal model developed in the laboratory offers insights for the development of a male contraceptive based on the indirect blockade of the actions of androgens on GRTH expression in germ cells without affecting other aspects of androgen action.
Joan Han's Unit on Metabolism and Neuroendocrinology conducts translational research on the genetic, metabolic, and neuroendocrine factors associated with pediatric obesity and neurocognitive development. The Unit studies rare genetic disorders associated with obesity (e.g., Alström, Bardet-Biedl, Prader-Willi, Smith-Magenis, and WAGR/11p deletion syndromes) as well as monogenic defects in the leptin signaling pathway (e.g., mutations affecting the genes for leptin, leptin receptor, melanocortin-4 receptor, and brain-derived neurotrophic factor) in order to gain insight into the neuroendocrine pathways that regulate human energy homeostasis and cognitive function. Candidate genes identified from these studies are further investigated in non-syndromic populations to determine whether common genetic variants are associated with differences in body composition and neurocognition. The goal of these investigations is to identify deficit-specific therapies for obesity and neurocognitive impairment.
Anil Mukherjee's Section on Developmental Genetics conducts both laboratory and clinical investigations into the hereditary neurodegenerative lysosomal storage disorders (LSDs) mostly affecting children. Current laboratory research in this Section focuses on the molecular mechanism(s) of pathogenesis of a group of neurodegenerative LSDs called neuronal ceroid lipofuscinoses (NCLs), commonly known as Batten disease. Mutations in at least 14 different genes cause various types of NCLs. At present, there is no effective treatment for any of the NCL types. The infantile NCL (or INCL) is an autosomal recessive LSD caused by mutations in the CLN1 gene, which encodes the lysosomal depalmitoylating enzyme, palmitoyl-protein thioesterase-1 (PPT1). PPT1 catalyzes the cleavage of thioester linkage in palmitoylated (S-acylated) proteins (constituent of ceroid), facilitating their degradation in lysosomes. Thus, PPT1 deficiency causes accumulation of ceroid in lysosomes, leading to INCL. Recently, the group identified a thioesterase-mimetic small molecule, N-tert-butyl hydroxylamine, which arrests neuropathology and extends lifespan in a mouse model of INCL and is thus a potential drug target for INCL. Gene-knockout and knock-in technologies as well as biochemical, molecular, and neurobiological techniques are utilized to conduct these studies. Translational research is emphasized.
Ida Owens' Section on Genetic Disorders of Drug Metabolism studies the biology of UDP-glucuronosyltransferase (UGT) isozymes. The Section's studies have shown that UGT isozymes, which are found primarily in liver, kidney, the gastrointestinal tract and steroid-responsive tissues, convert lipophilic endogenous substrates, dietary aromatic-like therapeutics, environmental pro-carcinogens, and contaminants derived from pyrolysates to water-soluble, excretable, non-toxic glucuronides; neurotoxic bilirubin is the most important endogenous substrate, followed by genotoxic catechol estrogens and elevated levels of dihydrotestosterone. The Section has demonstrated that each UGT isozyme examined so far requires phosphate signaling for activity. The Section's recent studies found that the human prostate luminal-cell UGT-2B15 and basal-cell UGT-2B17 have additional Src or Src/PKCε phosphorylation sites, that the isozymes are reversibly regulated via Src, and that UGT-2B15 exhibits pro-apoptotic activities whereas UGT-2B17 has the opposite function. The Section is therefore currently investigating the molecular details of UGT-2B15's apoptotic activity, considered critical to the prevention of prostate luminal cell transformation, ultimately to find clinically relevant translational markers.
Forbes Porter's Section on Molecular Dysmorphology studies a group of human and mouse malformation syndromes attributable to inborn errors of cholesterol synthesis. The most common of these disorders is the Smith-Lemli-Opitz syndrome (SLOS). The Section studies both basic science and clinical aspects of SLOS, with the goal of developing and testing therapeutic interventions for SLOS. The Section also studies basic and clinical aspects of Niemann-Pick disease, type C (NPC). The group has maintained an ongoing Natural History trial for NPC and SLOS since 2006 and 1998 respectively. The NPC Natural History trial was designed to investigate biochemical markers and clinical aspects of NPC that could be used as outcome measures in a future clinical trial. In collaboration with the National Center for Translational Medicine, the Section initiated a therapeutic trial of 2-hydroxypropyl-β-cyclodextrin in NPC1 subjects. In collaboration with extramural investigators, the Section was awarded a U01 grant to evaluate the safety and efficacy of histone deacetylase inhibitor therapy in NPC1 subjects.
Constantine Stratakis' Section on Endocrinology and Genetics investigates the genetic and molecular mechanisms leading to disorders affecting the adrenal cortex, with emphasis on those that are developmental, hereditary, and associated with adrenal hypoplasia or hyperplasia, multiple tumors, and abnormalities in other endocrine glands (especially the pituitary gland and, to a lesser extent, the thyroid gland). The Section has studied congenital adrenal hypoplasia caused by triple A syndrome; several endocrine deficiencies; familial hyperaldosteronism; adrenocortical and thyroid cancer; pituitary tumors; multiple endocrine neoplasia (MEN) syndromes affecting the pituitary, thyroid, and adrenal glands; and Carney complex (CNC), an autosomal dominant disease. Stratakis and colleagues first identified the regulatory subunit type 1-a (RIa) of protein kinase A (PKA) (the PRKAR1A gene), which is mutated in most CNC patients. The Section also found phosphodiesterase-11A and phosphodiesterase-8B (PDE11A and PDE8B) mutations in patients with isolated adrenal hyperplasia and Cushing's syndrome. A significant part of the Section's work focuses on cyclic AMP (cAMP)/PKA–stimulated signaling pathways and on PKA effects on tumor suppression and adrenal development and function. The Section's various studies take advantage of prkar1a and other gene mouse models. Most recently the Section identified defects of the genes PRKACA and PRKACB in CNC-related disorders and collaborated with a group in France in the identification of ARMC5 mutations in macronodular adrenal hyperplasia. Genome-wide searches for other genes responsible for CNC and related diseases of the adrenal, pituitary, and other endocrine glands are ongoing, including a large study on the genetics of gigantism.
Jack Yanovski's Section on Growth and Obesity studies metabolic and behavioral factors involved in body weight regulation and body composition during childhood in an effort to develop etiology-specific prevention and treatment approaches for pediatric obesity. The Section is investigating the effects of several genetic mutations in human pediatric obesity and murine models. Ongoing studies attempt to identify factors that predispose children to binge eating and related disorders. The Section's treatment and prevention studies are also directed at ameliorating conditions associated with hyperphagia.
In addition to research groups, PDEGEN also supports the Pediatric Endocrine fellowship program led by Constantine Stratakis and Maya Lodish. The fellowship in Pediatric Endocrinology is a three-year ACGME–accredited program providing comprehensive training in clinical patient management and guidance in the development of research skills. The NICHD program is based at one of the largest and most sophisticated research institutions in the United States. The NIH Clinical Center maintains clinical research protocols investigating the treatment of adrenal and pituitary tumors, congenital adrenal hyperplasia, precocious puberty, idiopathic juvenile osteoporosis, Cushing's syndrome, obesity, and others. Other institutions that participate in this training program include The Johns Hopkins University (JHU) Department of Pediatrics, Division of Pediatric Endocrinology; The Children's National Medical Center (CNMC), Division of Pediatric Endocrinology; and the cosponsoring institution, Georgetown University (GU), Department of Pediatrics. The facilities make available to our fellows pediatric endocrine, diabetes, oncology, metabolic, bone disorders, and other pediatric subspecialty clinics and consult services, as well as general pediatric inpatient and intensive care units.