This is an application for a Mentored Clinical Scientist Development Award for Dr. Geraldine Finlay to pursue research on the influence of tuberin on the control of smooth muscle cell growth in response to estrogen. Preliminary studies provide information that tuberin, the protein product of the TSC2 gene, is involved in regulating the growth response to estrogen and that MAP kinase is a vital signaling intermediate for this response. Further exploration of these observations will provide new insights into understanding the pathogenesis of diseases characterized by smooth muscle cell proliferation such as asthma, hypertension, atherosclerosis and lymphangioleiomyomatosis. Dr. Finlay will work in the laboratory of Dr. Barry Fanburg at the New England Medical Center, Tufts University School of medicine, who is an authority on smooth muscle biology and Dr David Kwiatkowski, a world expert in the genetics of TSC genes, at the Brigham and Women's Hospital, Harvard School of Medicine. Dr. Richard Karas, an expert in estrogen receptor cell signaling, at the New England Medical Center will also provide additional advisory support to Dr. Finlay. Facilities at each of the institutions will be readily available and participation in courses and conferences will be strongly encouraged. She will interact daily with Dr Fanburg and Dr. Kwiatkowski while spending time in each laboratory and will meet quarterly with an Advisory Committee. The proposed research will focus on the following specific aims: 1) To study the effects of tuberin on estrogen-mediated regulation of smooth muscle cell growth, 2)To assess the effects of tuberin on MAP kinase activation and MAP kinase function, 3)To investigate the effects of tuberin on the regulation of estrogen receptor function and 4) To study the effect of tuberin on estrogen-regulated vascular smooth muscle cell growth in vivo. These studies will allow Dr. Finlay to become educated and adept as a molecular biologist, give her the opportunity to complete and publish high quality research and to be competitive in acquiring a future independent research award while she assumes a staff position at this institution.
