MIS Regulation of Leydig Cell Development

描述(由申请人提供)：传统的观念认为，男性生殖结构(内外生殖器)依赖睾酮的分化和米勒抑制物质(MLS)介导的女性生殖结构(米勒导管)的退化是平行的，但独立的过程已经受到挑战，最近的数据表明这两条途径之间存在串扰。除了引起米勒管退行性变外，已有研究表明，在控制间质细胞发育的过程中，通过抑制其前体细胞的增殖和调节雄激素的生物合成，它发挥了不可或缺的作用。睾丸的这些睾丸活动对于获得足够的成人睾丸间质细胞的捐赠和正常的雄激素产生能力至关重要--这是男性生殖健康的基本方面。我们推测，在导致间质细胞停止增殖和促进终末分化功能获得的分子开关中，管理信息系统具有关键作用。我们的长期目标是了解在发育过程中，管理信息系统是如何在间质细胞中产生作用的。这项资助的具体目的是：1.通过实验性地去除间质细胞中的ALK功能来鉴定MISI型受体；2.鉴定和表征Smads在间质细胞中MISI信号转导中的作用。这项工作将加深我们对控制细胞增殖的新途径的理解，并为睾丸肿瘤的发生机制提供见解，这可能为控制未受调控的间质细胞增殖和肿瘤转化提供新的分子靶点。与公共卫生相关：增加对管理信息系统对雄激素合成和睾丸发育的旁分泌调节的了解，对治疗患有睾丸功能障碍的儿童具有治疗意义，并为患有双性条件的儿童提供新的管理方法。从这项工作中获得的见解可能会为患有睾丸癌的年轻男性和患有青春期和睾丸功能障碍的儿童提供替代疗法。此外，最近的研究报告说，世界范围内男性不育症的增加和精子数量的减少。我们的模型可能使我们能够识别由于这些内分泌干扰而导致的男性生殖健康的细微缺陷。由于雄激素的产生对男性生育能力至关重要，这项工作将提高我们对男性生殖健康和生育能力的理解。

DESCRIPTION (provided by applicant): The traditional concept that testosterone-dependent differentiation of male reproductive structures (internal and external genitalia) and Mullerian Inhibiting substance (MlS)-mediated regression of the female anlagen (Mullerian ducts) are parallel but independent processes has been challenged by recent data demonstrating cross-talk between these two pathways. In addition to causing Mullerian duct regression, MIS has been shown to play an integral role in controlling Leydig cell development by inhibiting proliferation of progenitor Leydig cells and modulating androgen biosynthesis. These testicular actions of MIS are critical for achieving an adequate adult endowment of Leydig cells and a normal capacity for androgen production- fundamental aspects of male reproductive health. We hypothesize that MIS has a critical role in the molecular switch that causes the cessation of Leydig cell proliferation and promotes acquisition of terminally differentiated function. Our long-term objectives are to understand how MIS elicits its actions in the Leydig cell in a developmental context. The Specific Aims of this grant are: 1. to identify the MIS type I receptors by experimental ablation of ALK function in Leydig cells; 2. to identify and characterize the role of Smads in MIS signal transduction in the Leydig cell. This work will enhance our understanding of a novel pathway for control of cellular proliferation and provide insights into the pathogenesis of testicular tumorigenesis, which may lead to new molecular targets for control of unregulated Leydig cell proliferation and neoplastic transformation. Relevance to Public Health: Increased knowledge of the paracrine regulation of androgen synthesis and testicular development by MIS has therapeutic implications for management of children with disorders of testicular function and offers novel approaches for management of children with intersex conditions. Insights gained from this work may lead to alternative therapies for young men with testicular cancer and children with disorders of puberty and testicular function. Moreover, recent studies report a world-wide increase in male infertility and decrease in sperm counts. Our models may enable us to identify subtle defects in male reproductive health due to these endocrine disrupters. Because androgen production is so critical to male fertility, this work will improve our understanding of male reproductive health and fertility.