MIS Regulation of Leydig Cell Development

描述（由申请人提供）：男性生殖结构（内外生殖器）的睾丸激素依赖性分化和缪勒管抑制物质（MlS）介导的女性胶原（缪勒管）的退化是平行但独立的过程，这一传统观念已被最近的数据所挑战，这些数据显示这两种途径之间存在交叉。除了引起苗勒管退化外，MIS已被证明通过抑制前体间质细胞的增殖和调节雄激素生物合成，在控制间质细胞发育中起着不可或缺的作用。MIS的这些睾丸活动对于获得足量的成年间质细胞和正常的雄激素生产能力至关重要——这是男性生殖健康的基本方面。我们假设MIS在导致间质细胞增殖停止和促进终分化功能获得的分子开关中起关键作用。我们的长期目标是了解MIS如何在发育背景下引发其在间质细胞中的作用。本奖助金的具体目的是：1。通过实验性消融间质细胞ALK功能鉴定MIS I型受体；2. 鉴定和表征Smads在间质细胞MIS信号转导中的作用。这项工作将增强我们对细胞增殖控制的新途径的理解，并为睾丸肿瘤发生的发病机制提供见解，这可能导致新的分子靶点来控制不受调节的间质细胞增殖和肿瘤转化。与公共卫生的相关性：MIS增加了对雄激素合成和睾丸发育的旁分泌调节的认识，对治疗睾丸功能障碍儿童具有治疗意义，并为治疗双性儿童疾病提供了新的方法。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，最近的研究报告称，全球范围内男性不育症增加，精子数量减少。我们的模型可能使我们能够识别由于这些内分泌干扰物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.