DEVELOPMENTAL CONTROL OF LEYDIG CELLS BY MIS

MIS 对间质细胞的发育控制

• 批准号: 6387373
• 负责人: Mary Min-chin Lee
• 金额: $ 10.3万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6387373
• 关键词: Leydig cells; Mullerian duct inhibiting substance; androgens; cell growth regulation; hormone receptor; hormone regulation /control mechanism; laboratory rat; receptor expression; reproductive development; steroid hormone biosynthesis; steroid hormone metabolism

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.

目前研究激素调节的建议 产后 Leydig 细胞发育融合了 Lee 博士长期以来的兴趣 在性别分化和性腺决定方面以及她的研究工作 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相关 睾丸决定、成熟和识别的调节 治疗双性障碍儿童的新方法。这 这笔赠款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。这 将投入更多的专门研究时间来获取专业知识 与她密切合作，熟悉不熟悉的方法（即流式细胞术） 合作者并扩大她对快速发展的科学的了解 与该项目相关的领域，例如细胞周期调控。 多个机构提供广泛的科学交流机会 MGH 和哈佛大学的研讨会系列和会议致力于 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 TGF-β 家族的成员， 导致男性胚胎性发育过程中苗勒氏管复旧 差异化。 Leydig 细胞增生和异常表型 然而，MIS 基因敲除小鼠的肿瘤形成揭示了 MIS 在 维持成熟睾丸中 Leydig 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 对治疗患有睾丸疾病的儿童的影响 发育或功能。该提案将检验以下假设： MIS 可防止 Leydig 细胞的无节制增殖并调节 类固醇生成酶。该提案的具体目的是阐明 MIS 在 Leydig 细胞增殖和类固醇生成调节中的作用 使用不同成熟度的原代 Leydig 细胞的体外细胞培养物 Leydig 细胞再生的阶段和体内模型。这些研究将 增加我们对细胞控制新途径的理解 产后睾丸的增殖和类固醇生成并提供见解 睾丸肿瘤发生的发病机制。 对睾丸发育的影响，该提案将检验假设 MIS 可以调节 Leydig 细胞增殖和类固醇生成。 在 一般来说，提案中的实验构思良好，假设 是可测试的。 根据她的科学和临床专业知识，李医生 有能力开展本提案中概述的研究。