Glutathione S-Tranferase signaling in VCD-induced ovotoxicity.

描述（由申请人提供） Aileen Keating博士是亚利桑那大学生理学系的博士后研究员。基廷博士将通过帕特里夏博士B奖的前两年的指导。霍耶和将共同指导博士唐娜张（亚利桑那大学）和博士乔迪缺陷（伊利诺伊大学）。霍耶博士的研究重点是环境化学物质对小腔前卵泡的影响。 具体来说，她的实验室已经开发了一个模型的环境外源性暴露在卵巢中，使用职业化学品4-乙烯基环己烯二环氧化物（VCD）。VCD选择性破坏大鼠和小鼠卵巢中的小腔前卵泡。 破坏小的腔前卵泡池可导致卵巢早衰（女性更年期提前）。本申请中概述的研究将补充但不与霍耶博士实验室进行的工作重叠。 随着近年来妇女晚育的趋势，减少生育年龄的环境暴露令人关切。 此外，更年期与心血管疾病、骨质疏松症、卵巢癌和抑郁症的风险增加有关。因此，加速更年期开始的化学物质是妇女关注的问题。 先前的研究已经调查了卵巢代谢在介导对卵毒性化学物质的反应中的作用。VCD可通过谷胱甘肽S-转移酶（GST）蛋白家族的作用在卵巢中代谢为无活性形式。 此外，GST还可以参与调节信号通路。本申请中提出的具体目标将研究VCD暴露后大鼠卵巢中GST信号传导的作用和调节。 具体目标1将研究GSTpi/mu是否与促凋亡蛋白形成蛋白质：蛋白质复合物，并确定这些蛋白质：蛋白质复合物是否响应VCD而解离并发生凋亡。 特异性目标2将确定VCD诱导的核磷酸化c-jun增加是否改变卵巢基因的转录活性，而特异性目标3将确定NRF 2蛋白在GSTpi和mu调节中的作用。这些发现将证明GST如何同时保护和增强VCD诱导的卵毒性。

DESCRIPTION (provided by applicant) This application is made to support the transition to independence of Dr. Aileen Keating, a post-doctoral fellow in the Department of Physiology at the University of Arizona. Dr. Keating will be mentored through the first two years of the award by Dr. Patricia B. Hoyer and will be co-mentored by Dr. Donna Zhang (University of Arizona) and Dr. Jodi Flaws (University of Illinois). Dr. Hoyer's research focuses on the effects of environmental chemicals on small pre-antral ovarian follicles. Specifically, her laboratory has developed a model of environmental xenobiotic exposure in the ovary, using the occupational chemical 4-vinylcyclohexene diepoxide (VCD). VCD selectively destroys small pre-antral follicles in the ovaries of rats and mice. Destruction of the small, pre-antral pool of ovarian follicles can lead to premature ovarian failure (early menopause in women). The research outlined in this application will complement but not overlap with work carried out in Dr. Hoyer's laboratory. With the trend in recent years for women to have children later in life, environmental exposures that reduce the reproductive years are of concern. Additionally, menopause is known to be associated with increased risk for cardiovascular disease, osteoporosis, ovarian cancer and depression. Thus, chemicals that accelerate the onset of menopause are of concern in women. Previous research has investigated a role for ovarian metabolism in mediating the response to ovotoxic chemicals. VCD can be metabolized to an inactive form in the ovary through the action of the Glutathione S-transferase (GST) family of proteins. Additionally, 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 of the NRF2 protein in regulation of GSTpi and mu. The findings will demonstrate how GST might simultaneously protect against and enhance VCD-induced ovotoxicity.