Carolyn Bondy, MD, Chief
The Developmental Endocrinology Branch (DEB) carries out a multidisciplinary, integrative program that combines clinical and basic research strategies to investigate the fundamental processes of human growth, development, and reproduction. The Branch brings together specialists in adult, pediatric, and reproductive endocrinology who study clinical disorders such as short stature, childhood obesity, endocrine tumors, Turner's syndrome, and premature ovarian failure. From careful study of patients at the bedside, DEB investigators develop novel insights into the molecular mechanisms of these disorders and into the development of new diagnostic and therapeutic approaches.
Greti Aguilera's Section on Endocrine Physiology focuses on molecular mechanisms of the hypothalamic stress response. Research during the past year has provided novel information on transcriptional regulation of corticotropin releasing hormone (CRH) and the physiological actions of vasopressin (VP) during chronic stress adaptation. The new findings, which demonstrate that activation of calcium/phospholipid-dependent pathways can potentiate both early transcriptional activation and late repression of the CRH gene in response to minor increases in cAMP, explain the rapid regulation of CRH expression by the non-cAMP-dependent regulators norepinephrine and glutamate, which are released in the paraventricular nucleus during stress. Concerning the effects of VP, against the general belief that VP mediates the regulation of pituitary ACTH secretion, studies using chronic administration of VP antagonists demonstrate that VP mediates mitogenic responses in the pituitary during chronic HPA axis stimulation while contributing to pituitary ACTH responses only to acute stress.
Jeffrey Baron's Section on Growth and Development had previously hypothesized that growth plate chondrogenesis slows with age because stem-like cells in the resting zone have a limited proliferative capacity. The Section has now directly evaluated the cell kinetics of chondrocytes and found that the number of these stem-like cells and their proliferation rate does decrease with age, a finding that provides direct support for the hypothesis. The group also investigated in detail p27/Kip1, a gene that might be involved in growth plate senescence and that encodes a cyclin-dependent kinase inhibitor. The investigators found that p27 is expressed by growth plate chondrocytes and that mice lacking a functional p27 gene exhibit increased body length and increased proliferation of growth plate chondrocytes, indicating that p27 is a negative regulator of growth plate chondrocyte proliferation.
Carolyn Bondy's Section on Women's Health Research investigates hormonal and genetic aspects of gender-based differences in cognitive, immunological, and metabolic functions and disease processes. Over the past year, the Section showed that important sex differences in metabolism and longevity appear to be attributable to differential X-chromosome origin in men (only maternal X) and women (both maternal and paternal X chromosomes). The lower longevity in men versus women correlates with an adverse metabolic profile, including atherogenic lipids and excess visceral adiposity, features not explained by sex steroid effects. Through the study of 45,X women with Turner's syndrome, the Section showed that differences in regional adiposity and lipid metabolism are mediated by the genomic imprinting of as yet unknown X-linked genes. In addition, the Section showed for the first time that individuals with monosomy for the X-chromosome have distinctive cardiac electrophysiological abnormalities, including fascicular block, accelerated AV conduction, T wave abnormalities, and prolongation of the rate-corrected QT interval (QTc), indicating that the second sex chromosome has profound effects on the cardiovascular system.
Lawrence Nelson's Unit on Gynecologic Endocrinology focuses on the pathophysiology and clinical management of spontaneous premature ovarian failure. The Unit demonstrated a highly significant association between circulating adrenal cortex autoantibodies and histologically confirmed autoimmune oophoritis, a mechanism of 46,XX spontaneous premature ovarian failure. Nelson's group is also investigating the physiology of the normal ovarian aging process. The investigators' work has shown that, of several markers of ovarian aging subjected to testing, age correlated most strongly with FSH-stimulated serum inhibin B levels. In work investigating the psychological response to the diagnosis of spontaneous premature ovarian failure, the group found that women with the condition perceive a need for clinicians to spend more time with them after making the diagnosis and to provide more information about the disorder.
Constantine Stratakis's Section on Genetics and Endocrinology works on Carney complex (CNC), a genetic syndrome associated with the development of several tumors of the heart, skin, breast, nervous system, and endocrine glands (thyroid, pituitary, gonads, and adrenal). The gene that is mutated in CNC participates in the structure of protein kinase A (PKA) and encodes the most common PKA-regulatory subunit (PRKARIA). During the past year, the Stratakis laboratory identified a new mutation in patients who did not exhibit PRKAR1A mutations but had bilateral adrenal tumors like those in CNC. Researchers found inactivating mutations of phosphodiesterase (PDE11A), a member of a 22-gene family of proteins that break down the cyclic nucleotides that control PKA. PDE11A appears to act as a tumor suppressor; thus, when its action is abolished, tumors develop as shown in pediatric and adult patients with bilateral adrenal tumors. This knowledge is novel and changes dramatically what was known about PDEs. In fact, the Stratakis laboratory is the first group to find any mutated PDE in a genetic disorder predisposing to tumors.
Jack Yanovski's Unit on Growth and Obesity studies metabolic and behavioral factors involved in determining body weight regulation and body composition during childhood. During the past year, the group showed that children with dual polymorphisms in the melanocortin 3 receptor (MC3R) gene exhibit decreased MC3R signal transduction and greater adiposity and insulin resistance than children with wild-type MC3R. The group is now investigating the effects of these mutations in a murine model. The laboratory also showed that serum BDNF is significantly lower in overweight youth and, in collaboration with investigators in Cambridge, UK, characterized a severely obese child with a chromosomal abnormality that affects the BDNF gene, suggesting that obesity is associated with BDNF haploinsufficiency. In addition, ongoing studies of psychological predictors showed conclusively that young children who report binge eating are at greater risk for obesity and that these children consume more calories during laboratory meal studies, providing the mechanism through which binge eating may promote children's excessive weight. Ongoing studies attempt to identify genetic abnormalities that predispose children to binge eating.
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