GROWTH CONTROL IN THE TESTIS AND MOLECULAR MECHANISMS OF TESTICULAR HOMEOSTASIS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。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。精子发生容易受到环境因素的破坏，这可能导致快速和大量的生殖细胞死亡。Akt1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。小鼠中Akt1的纯合缺失导致睾丸中自发凋亡水平升高。我们假设Akt1在睾丸生长、发育和毒物诱导损伤过程中作为存活因子起着关键作用。我们计划通过追求三个具体目标来解决这一假设。特异性Aim 1将确定Akt1在精子发生的发育过程中的作用。这将通过检查Akt1在发育和成年小鼠睾丸中的表达和定位来完成。其次，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发生时间的潜在差异。第三，利用建立的小鼠新生甲状腺功能减退模型，研究akt1依赖性对睾丸发育和大小的影响。目的2将确定Akt1在成人睾丸稳态中的功能意义。这将通过使用已建立的睾丸毒物性损伤模型来完成。我们将确定Akt1是否作为生殖细胞和/或支持细胞损伤后的促存活因子。目的3将鉴定影响睾丸发育和生长的akt1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体来实现，其次，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性睾丸损伤中Akt1存活途径的分子机制。

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.