MIS Regulation of Leydig Cell Development

MIS 对间质细胞发育的调节

• 批准号: 7097171
• 负责人: Mary Min-chin Lee
• 金额: $ 30.35万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7097171
• 关键词: DNA binding protein; Leydig cells; Mullerian duct inhibiting substance; biological signal transduction; cell differentiation; cell proliferation; genetically modified animals; hormone receptor; hormone regulation /control mechanism; immunoprecipitation; laboratory mouse; laboratory rat; protein structure function; reproductive development; subcellular fractionation; western blottings

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.

描述（由申请人提供）：传统观念认为，男性生殖结构（内生殖器和外生殖器）的睾酮依赖性分化和苗勒管抑制物质（MLS）介导的女性原基（苗勒氏管）的退化是平行但独立的过程。最近的数据表明这两种途径之间存在串扰，对此提出了挑战。除了引起缪勒氏管退化外，MIS 还被证明通过抑制间质祖细胞增殖和调节雄激素生物合成，在控制间质细胞发育中发挥不可或缺的作用。 MIS 的这些睾丸作用对于获得足够的成年间质细胞禀赋和正常的雄激素生成能力（男性生殖健康的基本方面）至关重要。我们假设 MIS 在导致 Leydig 细胞增殖停止并促进终末分化功能获得的分子开关中发挥关键作用。我们的长期目标是了解 MIS 如何在发育背景下在 Leydig 细胞中引发其作用。该资助的具体目标是： 1. 通过实验消除 Leydig 细胞中的 ALK 功能来鉴定 MIS I 型受体； 2. 鉴定和表征 Smads 在 Leydig 细胞 MIS 信号转导中的作用。这项工作将增强我们对控制细胞增殖的新途径的理解，并为睾丸肿瘤发生的发病机制提供见解，这可能会导致控制不受调节的间质细胞增殖和肿瘤转化的新分子靶标。与公共卫生的相关性：通过 MIS 增加对雄激素合成和睾丸发育的旁分泌调节的了解，对于治疗患有睾丸功能障碍的儿童具有治疗意义，并为治疗患有双性病症的儿童提供新方法。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带来替代疗法。此外，最近的研究报告称，世界范围内男性不育率增加，精子数量减少。我们的模型可以使我们识别由于这些内分泌干扰物而导致的男性生殖健康的微妙缺陷。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了解。