Mitochondrial Dynamics and Steroidogenesis

线粒体动力学和类固醇生成

• 批准号: 10573167
• 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/10573167
• 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 Proteins; Goals; Gonadal Steroid Hormones; Guanosine Triphosphate Phosphohydrolases; Headache; Healthcare Systems; Hormone Responsive; Infertility; Inner mitochondrial membrane; Iowa; LH Receptors; Lipids; Luteinizing Hormone; Male Genital Organs; Male Infertility; Mammals; Measures; Mediating; Medical center; Membrane; 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; Postdoctoral Fellow; 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 and Infertility; Shapes; Signal Induction; 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; transmission process

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 - 以下申请旨在启动Michele Plewes博士的研究职业 在VA内布拉斯加州爱荷华州卫生保健系统中，约翰·戴维斯（John Davis）的心态 研究职业科学家和过去30年中受尊敬的，由VA资助的生殖内分泌学家。 Plewes博士于2018年获得生物学博士学位，目前正在完成专业的博士学位培训 仅在生殖健康研究中，包括分子内分泌学和类固醇生成。 环境 - 内布拉斯加州大学医学中心毗邻奥马哈VA医疗中心 已经建立了牢固的科学关系来完成拟议的研究。研究 环境是合作和支持的，并有许多与其他研究合作的机会 科学家。特别是，Plewes博士将有机会讨论和介绍她的重要反馈作品 和VA高级研究人员的指导。在担任博士后同事的时期，Plewes博士已被邀请 在VA研究系列中两次介绍她的小说研究结果，并将继续寻求反馈 来自VA高级研究人员，包括她的VA导师。研究 - 性立体综合的失调和 分泌是男性和女性不孕的主要原因。不育会影响每6对夫妇中的1个， 在所有情况下，男性不育症在三分之一的情况下发挥了主要因素。此外，不育会影响约10％ 在美国，女性人口（610万）；大约有100,000名生殖年龄的女性退伍军人。 考虑到与与之相关的不孕症和次要影响的男人和女人的数量 性类固醇生物发生的失调理解调节PKA信号和动员的机制 类固醇生产的底物具有巨大的潜力，可以积极影响复制品健康和整体质量 生活。预计拟议的研究将提供有关扮演的片外侧作用的新信息 通过线粒体动力蛋白GTPases在卵巢/睾丸类固醇合成和功能的调节中。这 研究建议集中于识别负责传输信号的分子机制 从外部环境到线粒体，开始变化线粒体结构和功能，以及 然后将分子反应转化为类固醇生物合成的变化。拟议的目标测试总体 LH/PKA线粒体调节会影响线粒体结构，轨道间的假设 通信和最终类固醇生成。中心假设将通过两个具体目标进行检验。目的 1：确定S-OPA1在类固醇生成中的作用。我们将测试S-OPA1作为AKAP的假设 用于LH响应性细胞中的PKA。我们还将检验以下假设：线粒体PKA信号是需要的 最佳类固醇发生。 AIM 2：确定OMA1和S-OPA1在MICOS（线粒体接触位点）上的作用 和Cristae组织系统）复杂和类固醇生成。我们将测试OMA1和S-的假设 OPA1调节IMM内的线粒体MICOS复合物，该调节对于最佳 孕酮生物合成。为了衡量这一点，我们将定义线粒体参数，包括 Cristae组织，IMM超复合体组装，线粒体能量和线粒体核苷 安排。我们预测线粒体中MICOS复合物的破坏将破坏线粒体 能量学并最终破坏类固醇生成。这项研究支持了我们的长期目标 了解控制性类固醇类固醇生成的机制。这项研究的短期目标 正在发现LH/PKA信号传导如何影响线粒体和胆固醇动员的变化以达到最佳 孕酮和睾丸激素的产生。