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Genetic interrogation of conserved follicular factors for matrix metalloproteinase regulation and ovulation

基质金属蛋白酶调节和排卵的保守卵泡因子的遗传询问

基本信息

批准号：
9269226
负责人：
Jianjun Sun
金额：
$ 33.51万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-04 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9269226
关键词：
Anovulation Biological Assay Biological Models Calcium Cells Complex Contraceptive Agents Contraceptive methods Data Development Disease Drosophila genus Encapsulated Event Future Genes Genetic Genetic Screening Graafian Follicles Health Human Infertility Investigation Irregular Menstruation Knowledge Luteinization MAPK8 gene Mammalian Oviducts Mammals Matrix Metalloproteinases Methods Modeling Molecular Mus N-terminal NADPH Oxidase Nature Nuclear Receptors Oocytes Orthologous Gene Ovarian Ovarian Follicle Ovulation Oxidative Stress Pathway interactions Pharmacology Phosphotransferases Play Process Production Reactive Oxygen Species Regulation Role Rupture Signal Pathway Signal Transduction Signal Transduction Pathway System Testing Woman Work calmodulin-dependent protein kinase II fly gene function genetic approach genetic manipulation granulosa cell in vivo infertility treatment insight new therapeutic target novel oocyte maturation programs protein expression public health relevance spatiotemporal tool

项目摘要

DESCRIPTION (provided by applicant): Follicle rupture is the final step of the complex ovulation program, which releases fertilizable oocytes. Despite intensive study in the past four decades, a comprehensive understanding of the molecular mechanisms of follicle rupture is still lacking, in part due to the limitation of mammalian model systems to utilize genetic screens. We recently developed a novel Drosophila system that allows rapid application of genetic approaches to reveal precise details regarding the molecular events of follicular rupture. Moreover, recent studies from our lab have shown that the basic cellular and molecular mechanisms of ovulation are highly conserved from flies to humans; for instance, both systems require matrix metalloproteinase (Mmp) activity for follicle rupture. Leveraging the wealth of genetic tools and our ex vivo ovulation assay, this project will systematically interrogate conserved factors that are required for the precise regulation of Mmp activity and follicle rupture Our preliminary data reveals that an increase in intracellular free Ca2+ is required for Mmp activation but not expression. Conversely, follicular NADPH oxidase (Nox), which generates reactive oxygen species (ROS), and the oxidative stress-induced c-Jun N-terminal kinase (JNK) pathway regulate spatiotemporal Mmp protein expression. Therefore, we propose to 1) elucidate the conserved calcium-dependent signal transduction pathways that are required for Mmp activation, 2) investigate the role of follicular ROS and JNK signaling in Mmp expression, and 3) identify novel follicular factors for Mmp regulation and ovulation using genetic screens. This work will provide a comprehensive understanding of the ovarian signaling networks that precisely regulate Mmp activity and follicle rupture, which would be difficult in mammalian model systems. The conserved nature of these signaling pathways will allow the knowledge gained from this study to be further validated in mammalian and human ovulation. Therefore, this work will ultimately reveal promising new drug targets for the alleviation of anovulatory infertility orfor contraceptive development, both of which are highly relevant to human health.