Assistant Professor of Pediatrics and Molecular Biology and Pharmacology
The research efforts of our laboratory center on defining the role of neuropeptides produced by the hypothalamus in perinatal adaptation, reproduction, and behavior. To this end, we have developed murine transgenic and gene inactivation models to assess the in vivo functions of corticotropin-releasing hormone (CRH), oxytocin (OT), and adenylyl cyclase type VIII (AC8). Targeted inactivation of the CRH gene by homologous recombination in embryonic stem cells has resulted in production of a mouse with a markedly impaired adrenal response to stress. These animals lack circadian modulation of adrenal function, and demonstrate abnormal lung development in utero which can be rescued with steroid supplementation. The consequences of CRH and glucocorticoid deficiency for immune function, lung development, and metabolic regulation are currently being addressed. OT-deficient mice are viable, have normal fertility, and exhibit an unimpaired adrenal response to restraint or hemorrhage stress. Matings between OT-deficient male and female mice result in pregnancies which undergo delivery at the normal gestational age (19.5 d) without significant prolongation of the active phase of labor. Pups arising from these matings, however, die within the first several days of life, usually by 2 days after birth. Maternal mammary glands show engorgement with milk, and neonates stomachs are empty, consistent with a defect in milk let-down. Surprisingly, maternal behaviors including pup retrieval, nest building, and crouching over pups are grossly intact. By analyzing mice with combined cyclooxygenase-1 (COX-1) and OT deficiency, we have defined an essential role for COX-1 in determining the onset of murine labor by overcomimg the luteotrophic action of oxytocin in late gestation. As an alternate paradigm of impaired hypothalamic function, we are currently pursuing synaptic modification of neuropeptide secretion by second messenger pathways. The phenotype of mice with targeted inactivation of the calcium-stimulated AC8 isoform is currently being assessed.