GROWTH CONTROL IN THE TESTIS AND MOLECULAR MECHANISMS OF TESTICULAR HOMEOSTASIS

睾丸生长控制和睾丸稳态的分子机制

• 批准号: 7381356
• 负责人: MARY L HIXON
• 金额: $ 12.85万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381356
• 关键词: GROWTH; CONTROL; TESTIS; MOLECULAR; MECHANISMS

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall growth of the testis is based on the survival and proliferation of both germ and Sertoli cells. Spermatogenesis is susceptible to disruption by exposure to environmental agents which can result in rapid and massive germ cell death. Akt1 is a serine threonine kinase involved in the regulation of cell growth, proliferation, and apoptosis. Homozygous deletion of Akt1 in mice results in elevated levels of spontaneous apoptosis in the testis. We hypothesize that Akt1 plays a crtical role as a survival factor during testicular growth, development, and toxicant-induced injury. We plan to address this hypothesis by pursuing three Specific Aims. Specific Aim 1 will determine a role for Akt1 in the developmental onset of spermatogenesis. This will be accomplished by examining the expression and localization of Akt1 in the developing and adult mouse testis. Second, to examine histopathologic differences in germ cell and somatic cell number and potential differences in the timing of the onset of spermatogenesis. Third, using a well-established model which induces neonatal hypothyroidism in mice, to study Akt1-dependent effects on testis development and size. Aim 2 will establish the functional significance of Akt1 in adult testicular homeostasis. This will be accomplished by the use of established models of testicular toxicant-induced injury. We will determine if Akt1 acts as a pro-survival factor for germ and/or Sertoli cells following injury. Aim 3 will identify proteins in an Akt1-dependent signaling cascade which influences the development and growth of the testis. This will be accomplished by applying proteomic techniques to identify a signaling complex within the testis which regulates testis growth and development, and, second, to investigate the regulatory function of such a signaling network. Our overall goal is to understand the molecular mechanism(s) of an Akt1 survival pathway in toxicant-induced testicular injury.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。睾丸的整体生长是基于生殖细胞和支持细胞的存活和增殖。精子发生易受环境因素的破坏，这可能导致生殖细胞快速和大量死亡。Akt 1是一种丝氨酸/苏氨酸激酶，参与细胞生长、增殖和凋亡的调节。小鼠Akt 1纯合缺失导致睾丸自发性细胞凋亡水平升高我们假设Akt 1在睾丸生长、发育和毒物诱导的损伤中作为一种生存因子发挥着关键作用。我们计划通过追求三个具体目标来解决这个假设。特异性目的1将确定Akt 1在精子发生的发育起始中的作用。这将通过检查Akt 1在发育和成年小鼠睾丸中的表达和定位来实现。第二，检查生殖细胞和体细胞数量的组织病理学差异以及精子发生时间的潜在差异。第三，使用一个建立良好的模型，诱导新生儿甲状腺功能减退症的小鼠，研究Akt 1依赖的睾丸发育和大小的影响。目的2探讨Akt 1在成年睾丸稳态中的功能意义。这将通过使用已建立的睾丸毒物诱导损伤模型来实现。我们将确定Akt 1是否在损伤后作为生殖细胞和/或支持细胞的促存活因子。目的3将鉴定影响睾丸发育和生长的Akt 1依赖性信号级联中的蛋白质。这将通过应用蛋白质组学技术来确定睾丸内调节睾丸生长和发育的信号复合物来实现，第二，研究这种信号网络的调节功能。我们的总体目标是了解毒物诱导的睾丸损伤中Akt 1存活途径的分子机制。