STEROIDS REPRESS LH THROUGH PROTEIN/PROTEIN INTERACTIONS

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My immediate goal is to develop an equal background in research to what I had already devoted to clinical work. Therefore, I decided to pursue a doctoral degree with Dr. John Nilson at Case Western Reserve University (CWRU). My long term career goals are to combine my talents in basic science and clinical medicine in a faculty position at a veterinary teaching institution. The program in Dr. Nilson's laboratory and the environment at CWRU provide extraordinary access to any required resources. My research career development will be nurtured in this environment with the access to numerous structured meetings and training opportunities. Here I will learn how to critically evaluate data which will allow me to plan logical new experiments. In addition, I will receive invaluable training in writing succinct and meaningful scientific research papers and grant proposals. These achievements are critical in striving for my ultimate goal of becoming an independent researcher. This grant addresses the overall working hypothesis that the androgen and estrogen receptors repress lutropin expression through multiple protein-protein interactions in gonadotropes. Evidence indicates that AR in gonadotropes suppresses the alpha subunit promoter through protein-protein interactions that involve two distinct regulatory elements. However the identity of these critical proteins remains unknown. In Aim 1, the yeast two-hybrid approach will be used in both a directed and random fashion to screen for co-repressor proteins. In addition, we postulate that at least one phosphorylated residue of the AR is required for successful interaction with the co-repressor protein. We intend to test this hypothesis in Aim 2 by transiently transfecting AR phosphorylation mutants with the alpha subunit promoter in gonadotrope cells. Finally, we plan to exploit the knowledge gained on the alpha subunit suppression mechanism to enable us to unlock the mystery behind LHbeta regulation. In Aim 3, we propose to design transgenic mice in order to define the site and mechanism of steroidogenic regulation on the LHbeta subunit gene.