DEVELOPMENTAL CONTROL OF LEYDIG CELLS BY MIS

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The current proposal to investigate hormonal modulation of postnatal Leydig cell development integrates Dr. Lee's longstanding interest in sexual differentiation and gonadal determination and her research efforts to clarify a role of Mullerian Inhibiting Substance (MIS) in the developing testis. This work is relevant to Dr. Lee's long-term goals of understanding the regulation of testicular determination and maturation and identifying novel approaches to the management of children with intersex disorders. The funding provided by this grant will enable Dr. Lee to focus on her scientific development and concentrate on pursuing the objectives of this proposal. The increased dedicated research time will be invested in gaining expertise with unfamiliar methodology (i.e., flow cytometry) by working closely with her collaborators and in expanding her knowledge of rapidly advancing scientific areas that are relevant to this project, such as cell cycle regulation. Extensive opportunities for scientific exchange are available at several seminar series and conferences at MGH and Harvard that are devoted to Reproductive or Cell Biology as well as national scientific meetings. MIS a member of the TGF-beta family of growth and differentiation factors, causes involution of the Mullerian ducts during male embryonic sexual differentiation. The unexpected phenotypes of Leydig cell hyperplasia and neoplasia in MIS knockout mice, however, revealed novel roles for MIS in maintaining a normal complement of Leydig cells in the maturing testis and regulating androgen production. These actions of MIS may have therapeutic implications for the management of children with disorders of testicular development or function. This proposal will test the hypothesis that MIS prevents the unrestrained proliferation of Leydig cells and regulates steroidogenic enzymes. The specific aims of this proposal are to elucidate the role of MIS in the regulation of Leydig cell proliferation and steroidogenesis using in vitro cell cultures of primary Leydig cells at different maturational stages and an in vivo model of Leydig cell regeneration. These studies will increase our understanding of a novel pathway for control of cellular proliferation and steroidogenesis in the postnatal testis and provide insights into the pathogenesis of testicular tumorigenesis. effects in testicular development, and this proposal will test the hypotheses that MIS can regulate Leydig cell proliferation and steroidogenesis. In general, the experiments in the proposal are well conceived and the hypotheses are testable. Based on her scientific and clinical expertise, Dr. Lee is competent to carry out the studies outlined in this proposal.