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developmental endocrinology branch

Carolyn Bondy, MD, Chief

The mission of the Developmental Endocrinology Branch (DEB) is to investigate diseases that affect the processes of human growth, development, and reproduction. The branch has focused on genetic as well as on classical endocrine approaches to short stature, childhood obesity, endocrine tumors, Turner syndrome, and premature ovarian failure. Senior staff members are clinicians involved in patient care and training of clinical fellows, with weekly ward rounds and clinic conferences. From careful study of patients at the bedside, DEB investigators develop insights that lead to new “basic” approaches to elucidation of the molecular mechanisms of these disorders and to the development of new diagnostic and therapeutic approaches. Thus, the DEB’s multidisciplinary, integrative program combines direct patient care research and clinically oriented basic research strategies in order to translate basic biomedical research findings into practical bedside applications.

Greti Aguilera’s group, the Section on Endocrine Physiology, focuses on the molecular mechanisms controlling neuroendocrine components of the stress response. They demonstrated that cAMP stimulates CRH expression at transcriptional and post-transcriptional levels and contributes to limiting the duration of the transcriptional response through the production of cAMP-inducible early repressor (ICER). They also identified novel mechanisms by which vasopressin receptors activate the EGF receptor and MAP kinase pathway, a mechanism that in turn induces V1b receptor transcription.

Jeffrey Baron’s laboratory, the Unit on Growth and Development, had previously shown that longitudinal bone growth slows with age and eventually stops because growth plate chondrocytes undergo replicative senescence. Recently, the laboratory demonstrated that the mechanisms responsible for this replicative senescence in vivo are distinct from those causing replicative senescence in vitro and may involve loss of DNA methylation and associated epigenetic modifications.

Carolyn Bondy heads the Section on Growth and Metabolism, the Section on Women’s Health Research, and the Unit on Turner’s Syndrome. She and her coworkers have shown that young healthy women with monosomy X or Turner's syndrome have higher blood pressure and a distinctly more atherogenic lipid profile than age- and body fat–matched women with karyotypically normal premature ovarian failure, suggesting that a normal second X chromosome may protect women from atherosclerotic vascular disease through beneficial effects on blood pressure and lipid metabolism. In addition, Bondy’s team detected distinctive and novel cardiac conduction and repolarization abnormalities in Turner syndrome that provide new insight into the congenital heart defects associated with this disorder.

Lawrence Nelson’s unit, the Unit on Gynecologic Endocrinology, has elucidated the multifaceted nature of spontaneous premature ovarian failure by demonstrating that young women with this condition have significantly more symptoms of dry eye and eye surface damage than age-matched controls. In the laboratory, Nelson’s group defined the developmental expression and subcellular localization of mouse MATER, an antigen in a mouse model of autoimmune ovarian failure and an oocyte-specific protein essential for early development.

Jack Yanovski’s group, the Unit on Growth and Obesity, showed that polymorphisms in the melanocortin 3 receptor partially inactivate its function and are highly associated with pediatric obesity, particularly in African Americans. The data are the first to demonstrate the importance of this receptor for body weight regulation in humans. A second line of investigation found that, among children at risk for adult obesity, those reporting binge eating behaviors had a significantly greater risk of abnormal weight gain over a three-year observation period than children who did not report such behaviors. The novel data lay the groundwork for developing specific, etiology-based strategies for the prevention and treatment of pediatric obesity.

Constantine Stratakis’s group, the Section on Endocrinology and Genetics, showed that mouse models of PRKAR1A-downregulation replicate many of the findings of the human disease known as the Carney complex. DNA array studies have defined novel molecular pathways involved in adrenocortical tumorigenesis, with additional clinical and molecular studies identifying a new type of micronodular bilateral hyperplasia in infants and young children.