GROWTH CONTROL IN THE TESTIS AND MOLECULAR MECHANISMS OF TESTICULAR HOMEOSTASIS

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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.