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Home > Program in Developmental Endocrinology and Genetics

Program in Developmental Endocrinology and Genetics

Director: Forbes D. Porter, MD, PhD

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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. PDEGEN is also committed to providing superb training in the conduct of basic, translational, and clinical research. PDEGEN's training mission also involves supporting a nationally recognized, accredited Pediatric Endocrine Fellowship Training Program. PDEGEN investigators have diverse expertise ranging from biochemistry to molecular endocrinology and genetics to clinical obesity research.

PDEGEN has ten tenured investigators and two Assistant Clinical Investigators. The tenured investigators include Drs. Aguilera, Baron, Chou, Dufau, Klein, Mukherjee, Owens, Porter, Stratakis and Yanovski, all tenured investigators. Drs. Han and Delaney are initiating their scientific careers as Assistant Clinical Investigators. Dr. Maya Lodish, a prior PDEGEN Assistant Clinical Investigator, is now assisting our training mission as the Deputy Director of the Pediatric Endocrine Fellowship Training Program.

Greti Aguilera's Section on Endocrine Physiology focuses on the molecular mechanisms of the hypothalamic stress response. Research during the past year has yielded novel information on the transcriptional regulation of corticotropin releasing hormone (CRH) and the physiological actions of vasopressin (VP) during chronic stress adaptation. Contrary to the conventional view, Aguilera found that phosphorylation of the transcription factor CREB is not sufficient for activation of CRH transcription. Concerning the effects of VP, new findings demonstrate novel roles for the prominent increases in vasopressinergic activity during chronic stress. In addition to minor effects modulating pituitary adrenocorticotropic hormone secretion, the Section found that vasopressin mediates mitogenic responses in the pituitary and anti-apoptotic actions in the brain.

Jeffrey Baron's Section on Growth and Development investigates the cellular and molecular mechanisms governing childhood growth and development. Baron developed a novel approach to identify genes that regulate the human growth plate and thereby contribute to the normal variation in human height. The approach combines data from genome-wide association studies, human and mouse phenotype databases, and expression microarray studies of mouse and rat growth plates. This analysis implicated multiple genes involved in IHH-PTHrP, BMP, CNP, and GH-IGF1 signaling. Genes emerging from this analysis are strong candidates for the etiology of skeletal dysplasias. In other work, this group showed evidence that some of the same imprinted genes that serve to promote body growth early in life, MEST, PLAGL1, PEG3, and IGF2, are overexpressed in an embryonal cancer, rhabdomyosarcoma, and contribute to the abnormal growth of the malignant cells.

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), and glucose-6-phosphatase-beta (G6Pase-beta or G6PC3) deficiency, and develop gene therapies for these disorders. The G6PT/G6Pase-alpha complex maintains interprandial glucose homeostasis while the G6PT/G6Pase-beta complex maintains energy homeostasis and functionality of neutrophil and macrophages. Chou΄s group showed that G6PT is an endoplasmic reticulum (ER)-associated Pi-linked antiporter. This Section also showed that neutrophils express the G6PT/G6Pase-beta complex and inactivation of G6PT or G6Pase-beta leads to enhanced neutrophil apoptosis that underlies neutropenia in GSD-Ib and G6Pase-beta deficiency. More recently, Chou΄s group showed that G6Pase-beta is essential for energy homeostasis in neutrophils and macrophages. A G6Pase-beta deficiency prevents recycling of ER glucose to the cytoplasm, leading to neutrophil/macrophage dysfunction. Chou΄s Section has developed mouse models of GSD-Ia, GSD-Ib and G6Pase-beta-deficiency. Using GSD-Ia mice, the Section has developed an adeno-associated virus (AAV) vector-mediated gene transfer that corrects hepatic G6Pase-α 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 the initiation of pubertal onset in children. In collaboration with the Reproductive Endocrine Unit 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. This collaboration has resulted in the addition of the NIH as the second site in an existing protocol at MGH to phenotypically and genetically characterize subjects with IHH. The Unit uses molecular, cellular, and biochemical techniques to identify and characterize biological pathways that may contribute to the reactivation of GnRH secretion at puberty. Insights gained from these approaches will help to 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 (1) modes of transcriptional repression and derepression of receptors for human luteinizing hormone (LHR) and prolactin (PRLR) and (2) the functions of novel short PRLR inhibitory forms, identified by the Section, in physiological regulation and cancer. The Section also investigates mechanisms involved in Leydig cell function and the progression of spermatogenesis. 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. A low Mr acetylated protein identified as Histone 3 is recruited to PC4 during the activation state of the receptor. Other studies demonstrated conformational determinants required for the inhibitory action of the PRLR short form on prolactin-induced signaling through the long form. Studies revealed the essential role E2-enhanced complex of ERα dimer with SP1 and C/EBPß dimers in PRLR transcription Studies on the gonadotropin-regulated testicular helicase (GRTH/Ddx25), a protein discovered by this Section and shown to be essential for completion of spermatogenesis, demonstrated the protein multifunctionality (nuclear transport, storage/degradation of messages, and translation). It also prevents the Leydig cells from gonadotropin over stimulation of androgen through a recently demonstrated autocrine regulatory loop whereby androgen induced by gonadotropin increases GRTH transcription/expression which in turn reduces androgen production by enhancing StAR degradation. A Data base was created from differential studies of WT vs. KO of mRNAs associated to GRTH at polysomal sites of meiotic and haploid germ cells, for determination of its requirement on translation and/or transport of specific genes at these sites. Networks linked to GRTH derived from these studies could provide insights of male physiology and pathology. A data base for GRTH regulated miRNAs was also obtained. Also of note is the GRTH regulation of miR-469 silencing of chromatin remodelers Transition Protein 2 and Protamine 2 which is essential for their timely translation at later stages of spermatogenesis, providing a novel mechanism of GRTH function during germ cell development.

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 focuses on studying rare genetic disorders associated with obesity (e.g., Alström, Bardet-Biedl, Prader-Willi, 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 if common genetic variants are associated with differences in body composition and neurocognition. The goal of these investigations is identification of deficit-specific therapies for obesity and neurocognitive impairment.

David Klein's Section on Neuroendocrinology has played a dominant role in the circadian and pineal fields, maintaining a focus on the pineal gland and the key regulatory enzyme in melatonin synthesis, arylalkylamine N-acetyltransferase. Recently, the Section's interests broadened to characterize the pineal and retinal transcriptomes of vertebrates on a 24 hour basis and during development. Studies use cDNA microarrays and RNA Sequencing investigate the regulatory cascades that determine cell fate and maintain phenotype, in addition to the cascades dedicated to control of the daily global changes in gene expression. The daily changes in rodents involve nearly 1,000 genes, some of which exhibit 100-fold night/day differences in expression. Klein's Section uses a variety of approaches to analyze the cascades, including conditional knockouts and RNAi strategies. The Section has also characterized the microRNAs expressed in the pineal gland in order to determine their role in controlling the pineal transcriptome. The Section has initiated collaborations with other PDGEN researchers in an effort to introduce RNA Sequencing into ongoing research projects.

Anil Mukherjee's Section on Developmental Genetics conducts laboratory and clinical investigations into hereditary neurodegenerative lysosomal storage disorders mostly affecting children. The current laboratory research in this Section focuses on understanding the molecular mechanism(s) of pathogenesis of a group of neurodegenerative lysosomal storage disorders (LSDs) called neuronal ceroid lipofuscinosis (NCL), commonly known as Batten disease. Mutations in at least 13 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 a lysosomal 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, this group identified a thioesterase-mimetic that arrests neuropathology and markedly extends lifespan in a mouse model of INCL, and thus, it is a potential drug-target for INCL.

Ida Owens' Section on Genetic Disorders of Drug Metabolism studies primarily human UDP-glucuronosyltransferase (UGT) isozymes that detoxify numerous endogenous and exogenous chemical toxins/mutagens found endogenously, in our daily diet and environment. Whereas that group has continued to extend studies on required regulated phosphorylation of UGTs, their results have shown UGT-1A isozymes are solely dependent upon PKCs to support glucuronidation. Contrariwise, catalysis by 3 UGT-2B isozymes, which detoxify endogenous chemicals, is dependent upon Src-kinase alone or in combination with PKCs. UGT-2B7, distributed in mammary gland, is solely dependent upon Src-kinase to convert depurinating 4-OH-catechol-estrogens (4-OH-CE) without detectable conversion of 17β-estradiol; 2B7 expressed in src-free cells converts 4-OH-CE and 17β-estradiol at 15- and 9-fold higher rates, respectively. Prostate-distributed and dihydrotestosterone (DHT)-metabolizing isozymes UGT-2B15 and -2B17 require Src-kinase and PKCalpha/PKCepsilon for catalysis. Expression of 2B15 and 2B17 in Src-free cells demonstrates the former isozyme is unstable and becomes inactive, while 2B17 activity increases at least 2-fold under the Src-free conditions. For the prostate-distributed isozymes, Src kinase is pivotal to isozyme quality or its level of catalysis.

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. This group has had an ongoing Natural History trial since 2006. This study is designed to investigate biochemical markers and clinical aspects of NPC that could potentially be used as outcome measures in a future clinical trial. This section anticipates conducting a therapeutic trial of 2-hydroxypropyl-β-cyclodextrin in collaboration with the National Center for Translational Medicine in 2013.

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-α (RIα) of protein kinase A (PKA) (the PRKAR1A gene), which is mutated in most CNC patients. Most recently, the Section found phosphodiesterase-11A (PDE11A) mutations in patients with isolated adrenal hyperplasia and Cushing syndrome. A significant part of the Section s work focuses on cyclic AMP (cAMP)/PKA stimulated signaling pathways, PKA effects on tumor suppression, and/or development and the cell cycle. The Section's various studies take advantage of prkar1a and pde11a gene mouse models, in which the respective genes have been knocked out. Genome-wide searches for other genes responsible for CNC and related diseases of the adrenal, pituitary and other endocrine glands are ongoing.

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 supported the Pediatric Endocrine fellowship program lead by Drs. Stratakis and 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 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, finally, the cosponsoring institution, Georgetown University (GU) Department of Pediatrics. These facilities make available to our fellows pediatric endocrine, diabetes, oncology, metabolic, bone disorders and other pediatric subspecialty clinics and consult services, and general pediatric inpatient and intensive care units.

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