DEVELOPMENTAL CONTROL OF LEYDIG CELLS BY MIS

目前的建议，调查激素调节， 出生后Leydig细胞发育整合了Lee博士长期以来的兴趣 在性分化和性腺决定以及她的研究工作中 为了阐明苗勒管抑制物质（MIS）在发育中的作用， 睾丸这项工作与李博士的长期目标有关， 睾丸决定和成熟的调控及鉴定 新的方法来管理儿童与双性障碍。的 该补助金提供的资金将使李博士能够专注于她的科学研究 发展，并集中精力实现本提案的目标。的 将投入更多的专门研究时间， 不熟悉的方法（即，流式细胞术）与她密切合作， 合作者和扩大她的知识，迅速发展的科学 与本项目相关的领域，如细胞周期调节。 科学交流的广泛机会在几个 在MGH和哈佛的系列研讨会和会议，致力于 生殖或细胞生物学以及国家科学会议。 MIS是生长和分化因子的TGF-β家族的成员， 在男性胚胎性交时导致苗勒管退化 分化睾丸间质细胞增生的非预期表型和 然而，MIS基因敲除小鼠的肿瘤形成揭示了MIS在 在成熟的睾丸中维持间质细胞的正常补充， 调节雄激素的产生。MIS的这些作用可能具有治疗作用。 对睾丸疾病儿童治疗的意义 发展或功能。这一提议将检验以下假设： MIS可防止间质细胞的无限制增殖，并调节 类固醇生成酶。本提案的具体目的是阐明 MIS在Leydig细胞增殖和类固醇激素合成中的作用 使用不同成熟度的原代Leydig细胞的体外细胞培养物， 阶段和Leydig细胞再生的体内模型。这些研究将 增加了我们对控制细胞凋亡的新途径的理解， 增殖和类固醇生成的研究， 睾丸肿瘤发生的发病机制 睾丸发育的影响，这项建议将测试假设 MIS可以调节Leydig细胞增殖和类固醇合成。 在 总的来说，建议中的实验构思良好，假设 是可测试的。 基于她的科学和临床专业知识，李博士是 有能力开展本提案中概述的研究。

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.