Glutathione S-Tranferase signaling in VCD-induced ovotoxicity.

这项申请是为了支持艾琳·基廷博士的过渡，她目前是哈佛大学的博士后研究员 亚利桑那大学生理学系成为独立学院的助理教授 爱荷华州立大学动物科学系。基廷博士将被指派两名导师参加 她是动物科学系的学生，并将与他们合作开展教学和研究活动。这个 霍耶博士是她的博士后导师，他的研究重点是环境化学物质对Small的影响 腔前卵泡。霍耶博士使用职业化学品4-乙烯基环己烯二环氧化物(VCD)， 作为卵巢环境异种暴露的模型。VCD选择性破坏腔前小卵泡 在啮齿动物卵巢中，导致卵巢早衰(类似于女性的早绝经期)。Dr。 基廷的研究将继续补充霍耶博士的研究，但不会与之重叠。更年期是已知的 与心血管疾病、骨质疏松症、卵巢癌和 抑郁症。因此，减少生育年限并加速更年期开始的化学物质，如 作为VCD，在女性中是值得关注的。VCD可以在谷胱甘肽的作用下代谢成不活跃的形式 S转移酶(GST)蛋白。GSTS还可以参与信号通路的调节。具体目标 本应用将研究GST信号在大鼠卵巢中的作用和调节 对VCD曝光的反应。特定目标1将研究GSTpi/Mu是否形成蛋白质：蛋白质 与促凋亡蛋白的复合体，并确定这些蛋白是否对VCD做出反应：蛋白质 复合体解离，发生细胞凋亡。特定目标2将确定VCD诱导的核增加 磷酸化的c-jun改变卵巢基因的转录活性，而特异性靶点3将决定 NRF2蛋白在GSTpi和Mu调节中的作用。基廷博士将把具体目标1和3扩展到 包括关于GST参与其他两种化学物质代谢的初步研究 卵巢损伤和卵泡破坏、7，12-二甲基苯并[a]蒽(DMBA)和磷酰胺 芥末(PM)。

This application is made to support the transition of Dr. Aileen Keating, currently a post-doctoral fellow in the Department of Physiology at the University of Arizona to independence as an Assistant Professor in the Department of Animal Science at Iowa State University. Dr. Keating will be assigned two mentors in the Department of Animal Science and will work with them to develop her teaching and research activities. The research of Dr. Hoyer, her postdoctoral mentor, focuses on the effects of environmental chemicals on small pre-antral ovarian follicles. Dr. Hoyer uses the occupational chemical, 4-vinylcyclohexene diepoxide (VCD), as a model of ovarian environmental xenobiotic exposure. VCD selectively destroys small pre-antral follicles in rodent ovaries, leading to premature ovarian failure (analogous to early menopause in women). Dr. Keating's research will continue to complement but not overlap with that of Dr. Hoyer. Menopause is known to be associated with increased risk for cardiovascular disease, osteoporosis, ovarian cancer and depression. Thus, chemicals that reduce reproductive years and accelerate the onset of menopause, such as VCD, are of concern in women. VCD can be metabolized to an inactive form by the action of Glutathione S-transferase (GST) proteins. GSTs can also participate in regulating signaling pathways. The specific aims proposed in this application will investigate the role and regulation of GST signaling in the rat ovary in response to VCD exposure. Specific Aim 1 will investigate whether GSTpi/mu form protein:protein complexes with pro-apoptotic proteins and to determine if, in response to VCD, these protein:protein complexes dissociate and apoptosis occurs. Specific Aim 2 will determine if VCD-induced increased nuclear phosphorylated c-jun alters transcriptional activity of ovarian genes, while Specific Aim 3 will determine the role ofthe NRF2 protein in regulation of GSTpi and mu. Dr. Keating will expand specific aim 1 and 3 to include preliminary studies on the involvement of GST's in metabolism of two other chemicals that cause ovarian damage and follicle destruction, 7,12-dimethylbenz[a]anthracene (DMBA) and phosphoramide mustard (PM).