Glutathione S-Tranferase signaling in VCD-induced ovotoxicity.

VCD 诱导的卵毒性中的谷胱甘肽 S 转移酶信号传导。

基本信息

批准号：
8272625
负责人：
Aileen Frances Keating
金额：
$ 24.9万
依托单位：
IOWA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-10 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8272625
关键词：
Address Animals Anthracenes Antral Apoptosis Apoptotic Arizona Biological Assay Cell Nucleus Cessation of life Chemical Exposure Chemicals Complement Complex Cytoplasm Data Educational process of instructing Enzymes Excision Exposure to Family Female Funding Gene Targeting Genes Glutathione Glutathione S-Transferase Iowa JUN gene Knockout Mice Knowledge Location MAPK8 gene Malignant neoplasm of ovary Menopause Mental Depression Mentors Metabolism Microsomal Epoxide Hydrolase Modeling Mus Neonatal Nuclear Occupational Osteoporosis Ovarian Ovarian Follicle Ovary Phase Phosphoramide Mustard Phosphoramide Mustards Physiology Play Postdoctoral Fellow Premature Ovarian Failure Primordial Follicle Promoter Regions Protein Family Proteins Rattus Regulation Reproductive Health Research Research Activity Rodent Role Science Signal Pathway Signal Transduction Signaling Protein System Toxic effect UV Radiation Exposure Universities Woman Work Xenobiotic Metabolism Xenobiotics base cardiovascular disorder risk design dimethylbenzanthracene environmental chemical novel ovotoxicity prevent pro-apoptotic protein professor promoter protein complex reproductive research study response transcription factor

项目摘要

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).

此申请是为了支持 Aileen Keating 博士的过渡，她目前是该研究所的博士后研究员。亚利桑那大学生理学系独立担任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动物科学系并将与他们合作发展她的教学和研究活动。这她的博士后导师 Hoyer 博士的研究重点是环境化学物质对小动物的影响。窦前卵泡。 Hoyer 博士使用职业化学品 4-乙烯基环己烯二环氧化物 (VCD)，作为卵巢环境异生素暴露的模型。 VCD选择性破坏小窦前卵泡在啮齿动物卵巢中，导致卵巢早衰（类似于女性提前绝经）。博士。基廷的研究将继续补充霍耶博士的研究，但不会重叠。更年期是众所周知的与心血管疾病、骨质疏松症、卵巢癌和卵巢癌的风险增加有关沮丧。因此，减少生育年龄并加速更年期发生的化学物质，例如像VCD一样，受到女性的关注。 VCD 可通过谷胱甘肽的作用代谢为无活性形式 S-转移酶 (GST) 蛋白。 GST 还可以参与调节信号通路。具体目标本申请中提出的研究将研究 GST 信号在大鼠卵巢中的作用和调节对 VCD 曝光的反应。具体目标 1 将研究 GSTpi/mu 是否形成蛋白质：蛋白质与促凋亡蛋白形成复合物，并确定这些蛋白：蛋白是否响应 VCD 复合物解离并发生细胞凋亡。具体目标 2 将确定 VCD 是否诱导核增加磷酸化 c-jun 改变卵巢基因的转录活性，而特定目标 3 将决定 NRF2 蛋白在 GSTpi 和 mu 调节中的作用。基廷博士将具体目标 1 和 3 扩展至包括关于 GST 参与其他两种化学物质代谢的初步研究，这些化学物质会导致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（下午）。