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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. PDEGEN is also committed to providing superb 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.
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. Drs. Han and Delaney are beginning their scientific careers as Assistant Clinical Investigators. Dr. Maya Lodish, a prior PDEGEN Assistant Clinical Investigator, is now assisting PDEGEN’s 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 yielded novel information on the transcriptional regulation of corticotropin releasing hormone (CRH) and glucocorticoid feedback. Aguilera found that, contrary to the conventional view, activation of CRH transcription requires, in addition to phosphorylation of the transcription factor CREB, the co-activator transducer of regulated CREB activity and that glucocorticoids repress CRH transcription indirectly rather than by interaction of the glucocorticoid receptor with the CRH promoter. The Section also found that episodic transcription of proteins involved in adrenal glucocorticoid synthesis and rapid glucocorticoid feedback at the pituitary levels are part of the mechanism controlling ultradian regulation of adrenal glucocorticoid secretion.
Jeffrey Baron's Section on Growth and Development investigates the cellular and molecular mechanisms governing childhood growth and development. One goal of this work is to gain insight into the many human genetic disorders that cause childhood growth failure or overgrowth. Further investigation of the identified growth-limiting mechanisms may also lead to broader medical applications, because disruption of these mechanisms may contribute to oncogenesis, and conversely transient therapeutic suspension of growth-limiting mechanisms in adult cells might be used to achieve tissue regeneration. The Section identified a juvenile multi-organ genetic program, which involves the downregulation of a large set of growth-promoting genes, and obtained evidence that the program helps explain the rapid body growth of early life and the subsequent slowing of growth with age. Recently, the group showed that the growth-limiting program is orchestrated by the transcription factor E2f3 and that failure of regulation by E2F3 can contribute to the growth of specific malignancies.
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 Pi-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 neutropenia in GSD-Ib and G6Pase-beta deficiency. Chou's group further 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. More recently, Chou's group showed that the mechanism of neutrophil dysfunction in GSD-Ib arises from activation of the HIF-1α/PPAR-γ 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-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 (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). 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 on transcriptional regulation/expression of PRLR in breast cancer; (iii) mechanisms involved on 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 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. A low-molecular-weight acetylated protein, identified as histone 3 (H3), is recruited to PC4 during the activation state of the receptor. Acetylated H3 presence in the complex in association to chromatin was determined. 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 therapy-refractory states 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 through an autocrine regulatory loop. A transgenic animal model developed in this 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.
David Klein's Section on Neuroendocrinology has played an important 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 using 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 also characterized the microRNAs expressed in the pineal gland in order to determine their role in controlling the pineal transcriptome. The Section 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 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 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 the 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, the group identified a thioesterase mimetic that arrests neuropathology and markedly extends lifespan in a mouse model of INCL and is thus 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 and in our daily diet and environment. The group continued to extend studies on required regulated phosphorylation of UGTs, and their results showed that UGT-1A isozymes are solely dependent upon PKCs to support glucuronidation. Catalysis by three UGT-2B isozymes, which detoxify endogenous chemicals, is however dependent on Src-kinase alone or in combination with PKCs. UGT-2B7, distributed in mammary gland, is solely dependent on the Src-kinase to convert depurinating 4-OH-catechol-estrogens (4-OH-CE) but without detectable conversion of 17β-estradiol; UGT-2B7, expressed in Src-free cells, converts 4-OH-CE and 17β-estradiol at 15- and 9-fold higher rates, respectively. The prostate-distributed, dihydrotestosterone (DHT)-metabolizing isozymes UGT-2B15 and UGT-2B17 require Src-kinase and PKCalpha/PKCepsilon for catalysis. Expression of UGT-2B15 and UGT-2B17 in Src-free cells demonstrates that the former isozyme is unstable and becomes inactive, while UGT-2B17 activity increases at least two-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. 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 patients.
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'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, development, or 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 supports the Pediatric Endocrine fellowship program led 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 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.