Mitochondrial Dynamics and Steroidogenesis

线粒体动力学和类固醇生成

• 批准号: 10359058
• 负责人: Michele R Plewes
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10359058
• 关键词: A kinase anchoring protein; Adenylate Cyclase; Adipocytes; Adrenal Glands; Affect; Age; Anabolism; Attenuated; Binding; Biogenesis; Biology; C-terminal; Cells; Cholesterol; Collaborations; Communication; Complex; Coupled; Couples; Crista ampullaris; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Docking; Doctor of Philosophy; Dynamin; Embryonic Development; Endocrinologist; Endocrinology; Environment; Enzymes; Erectile dysfunction; Feedback; Female; Funding; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Goals; Gonadal Steroid Hormones; Guanosine Triphosphate Phosphohydrolases; Healthcare Systems; Hormone Responsive; Infertility; Inner mitochondrial membrane; Iowa; LH Receptors; Lipids; Luteinizing Hormone; Male Infertility; Mammals; Measures; Mediating; Medical center; Mentors; Mentorship; Metabolic; Metalloproteases; Migraine; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Morphology; Nebraska; OPA1 gene; Organelles; Outer Mitochondrial Membrane; Ovarian; Ovary; Phosphorylation; Pituitary Hormones; Play; Population; Positioning Attribute; Pregnancy; Production; Progesterone; Protein Isoforms; Proteins; Quality Control; Quality of life; Regulation; Reproductive Health; Research; Research Personnel; Research Proposals; Research Support; Role; Scientist; Series; Sexual Dysfunction; Shapes; Signal Transduction; Site; Steroid biosynthesis; Steroids; Structure; System; Tertiary Protein Structure; Testing; Testis; Testosterone; Time; Tissues; Translating; Transmembrane Domain; United States; Universities; Uterus; Veterans; Woman; Work; Zinc; career; design; early pregnancy loss; female reproductive system; implantation; knock-down; male; men; novel; post-doctoral training; protein activation; protein protein interaction; receptor; reproductive; response; testosterone biosynthesis

Candidate - The following application is intended to initiate the research career of Michele Plewes, PhD, within the VA Nebraska Iowa Health Care System under the mentorship of John Davis, PhD, a VA Senior Research Career Scientist and a well-respected, VA-funded reproductive endocrinologist for the past 30 years. Dr. Plewes received her PhD in Biology in 2018 and is currently completing her postdoctoral training focused exclusively in reproductive health research, including molecular endocrinology and steroidogenesis. Environment - The University of Nebraska Medical Center is adjacent to the Omaha VA Medical Center where strong scientific relationships have been established to complete the proposed studies. The research environment is collegial and supportive with a multitude of opportunities for collaboration with other research scientists. Specifically, Dr. Plewes will have the opportunity to discuss and present her work for crucial feedback and direction from senior VA researchers. In her time as a postdoctoral associate, Dr. Plewes has been invited to present her novel research findings twice at the VA research seminar series and will continue to seek feedback from senior VA researchers, including her VA mentors. Research – Dysregulation of sex steroid synthesis and secretion is a leading cause of infertility in both male and females. Infertility affects 1 in every 6 couples, with male infertility playing a primary factor in a third of all cases. Moreover, infertility affects about 10 percent of the female population (6.1 million) in the United States; about 100,000 female Veterans of reproductive age. Considering the number of men and women who suffer from infertility and secondary affects associated with dysregulation of sex steroid biogenesis understanding mechanisms that regulate PKA signaling and mobilization of substrate for steroid production hold great potential to positively impact reproductive health and overall quality of life. The proposed studies are expected to provide new information about the extramitochondrial role played by mitochondrial Dynamin-GTPases in regulation of ovarian/testicular steroid synthesis and function. This research proposal centers on the identification of the molecular mechanisms responsible for transmitting signals from the outside environment to the mitochondria, initiating changes in mitochondrial structure and function, and then translating molecular responses into changes in steroid biosynthesis. The proposed aims test the overall hypothesis that LH/PKA regulation of mitochondria impacts mitochondrial structure, inter-organelle communication and ultimately steroidogenesis. The central hypothesis will be tested by two specific aims. Aim 1: Determine the role of S-OPA1 in steroidogenesis. We will test the hypothesis that S-OPA1 serves as an AKAP for PKA in LH-responsive cells. We will also test the hypothesis that mitochondrial PKA signaling is required for optimal steroidogenesis. Aim 2: Determine the role of OMA1 and S-OPA1 on MICOS (Mitochondrial Contact Site and Cristae Organizing System) complex and steroidogenesis. We will test the hypothesis that OMA1 and S- OPA1 regulate mitochondrial MICOS complexes within the IMM and this regulation is essential for optimal progesterone biosynthesis. In order to measure this, we will have defined mitochondrial parameters including cristae organization, IMM Supercomplexes assembly, mitochondrial energetics and mitochondrial nucleoid arrangement. We predict disruption of MICOS complexes in mitochondria will disrupt the mitochondrial energetics and ultimately disrupt steroidogenesis. This research supports our long-term objectives to fully understand the mechanisms controlling steroidogenesis of sex steroids. The short-term goals of this research are to discover how LH/PKA signaling induce changes in mitochondria and cholesterol mobilization for optimal progesterone and testosterone production.

候选人-以下应用程序旨在启动米歇尔Plewes，博士的研究生涯， 在弗吉尼亚州内布拉斯加州爱荷华州卫生保健系统的指导下，约翰戴维斯博士，弗吉尼亚州高级 研究职业科学家和一个备受尊敬的，VA资助的生殖内分泌学家在过去的30年。 博士Plewes于2018年获得生物学博士学位，目前正在完成博士后培训， 专门用于生殖健康研究，包括分子内分泌学和类固醇生成。 环境-内布拉斯加大学医学中心毗邻奥马哈VA医疗中心， 为完成拟议的研究，已建立了强有力的科学关系。研究 环境是合议和支持与其他研究合作的机会众多 科学家具体来说，Plewes博士将有机会讨论和介绍她的工作，以获得重要的反馈 和VA高级研究人员的指导。在她作为博士后助理的时间里，Plewes博士被邀请 在退伍军人事务部研究研讨会系列上两次介绍她的新研究成果，并将继续寻求反馈 包括她的退伍军人事务部导师研究-性类固醇合成失调和 分泌物是男性和女性不育的主要原因。每6对夫妇中就有1对患有不孕症， 男性不育是三分之一病例的主要原因。此外，不孕症影响了大约10%的 美国的女性人口（610万）;大约10万育龄女性退伍军人。 考虑到患有不孕症的男女人数以及与不孕症相关的继发性影响， 了解调节PKA信号和动员的机制 类固醇生产的底物具有巨大的潜力，对生殖健康和整体质量产生积极影响 生命这些研究有望提供有关线粒体外作用的新信息 通过线粒体动力蛋白-GTP酶调节卵巢/睾丸类固醇的合成和功能。这 一项研究计划的中心是确定负责传递信号的分子机制 从外部环境到线粒体，引发线粒体结构和功能的变化， 然后将分子反应转化为类固醇生物合成的变化。拟议的目标测试了总体 线粒体LH/PKA调节影响线粒体结构、细胞器间 交流和最终类固醇合成。中心假设将通过两个具体目标进行检验。目的 1：确定S-OPA 1在类固醇生成中的作用。我们将检验S-OPA 1作为AKAP的假设 LH-反应细胞中的PKA。我们还将检验线粒体PKA信号传导是细胞凋亡所必需的这一假设。 最佳类固醇合成目的2：确定OMA 1和S-OPA 1在线粒体接触位点（MICOS）中的作用 和嵴组织系统）复合体和类固醇生成。我们将检验OMA 1和S- OPA 1调节IMM内的线粒体MICOS复合物，并且这种调节对于最佳的 黄体酮生物合成。为了测量这一点，我们将定义线粒体参数，包括 嵴结构，IMM超复合体组装，线粒体能量学和线粒体类核 安排我们预测线粒体中MICOS复合物的破坏将破坏线粒体 并最终破坏类固醇合成。这项研究支持我们的长期目标， 了解控制性类固醇激素合成的机制。本研究的短期目标 目的是发现LH/PKA信号如何诱导线粒体和胆固醇动员的变化， 孕酮和睾酮的产生。