Biomedical Sciences Graduate Program | University of California, San Francisco

My laboratory works on the neuroendocrine mechanisms which control ovulation in mammals. Reproductive function is driven by the pulsatile release of the hypothalamic hormone GnRH. We showed that pulsatile release of GnRH was an intrinsic property of the GnRH neurons. We are currently studying the molecular basis for the biological clock timing the release of GnRH every 25 minutes. Current findings suggest that the clock consists of the generation of cAMP and the activation of downstream signaling pathways, including cAMP gated cation channels and protein kinase A. We use genetic approaches to alter the cAMP signaling pathway e.g. expressing a phosphodiesterase to hydrolyze cAMP. We have now shown that lowering cAMP levels in GT1 cells or transgenic rats by expressing a phosphodiesterase resulted in the inhibition of pulsatile GnRH release. The lowered gonadotropin levels in the transgenic rats results in the formation of polycystic ovaries.

A second research focus is to develop therapeutic agents that inhibit the formation of a new blood supply (angiogenesis) to tumors. We showed that the 16 kDa N-terminal fragment of prolactin (16K PRL) is a potent antiangiogenic factor. In capillary endothelial cells 16K PRL inhibits VEGF-induced cell proliferation, activates PAI-1 expression and induces apoptosis. We showed that 16K hPRL inhibited VEFG-induced cell proliferation by blocking Ras activation and activated apoptosis by activating a caspase cascade. We are utilizing FRET to understand how these complex signaling events are integrated at the level of the plasma membrane of capillary endothelial cells.