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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).

此申请是为了支持艾琳·基廷博士的过渡，目前她是美国国家航空航天局的博士后研究员。在亚利桑那大学生理学系独立担任助理教授，爱荷华州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，以发展她的教学和研究活动。的她的博士后导师霍耶博士的研究重点是环境化学品对小动物的影响。窦前卵泡。霍耶博士使用职业化学品，4-乙烯基环己烯二环氧化物（VCD），作为卵巢环境异生物质暴露的模型。VCD选择性破坏小腔前卵泡在啮齿动物卵巢中，导致卵巢过早衰竭（类似于女性的早期绝经）。博士基廷的研究将继续与霍耶博士的研究相辅相成，但不会重叠。更年期是已知的与心血管疾病、骨质疏松症、卵巢癌的风险增加有关，萧条因此，减少生育年龄和加速绝经期的化学物质，如VCD，在女性中引起关注。VCD可在谷氨酸的作用下代谢为无活性形式 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GST π/mu是否形成蛋白质：蛋白质与促凋亡蛋白的复合物，并确定这些蛋白质：复合物解离并发生凋亡。具体目标2将确定VCD诱导的核增加是否磷酸化的c-jun改变卵巢基因的转录活性，而特异性目的3将决定卵巢癌的发生。 NRF 2蛋白在调节GST π和μ中的作用。基廷博士将扩大具体目标1和3，包括对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）。