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 - 以下申请旨在开启 Michele Plewes 博士的研究生涯， 在退伍军人管理局高级人员约翰·戴维斯博士的指导下，在退伍军人管理局内布拉斯加州爱荷华州医疗保健系统内 过去 30 年来，一直担任研究职业科学家和受 VA 资助的受人尊敬的生殖内分泌学家。 Plewes 博士于 2018 年获得生物学博士学位，目前正在完成她的博士后培训，重点关注 专门从事生殖健康研究，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退伍军人医疗中心， 已经建立了牢固的科学关系来完成拟议的研究。 具有合作性和支持性的环境，有大量与其他研究合作的机会 具体来说，Plewes 博士将有机会讨论和展示她的工作以获得重要反馈。 Plewes 博士在担任博士后期间受到了 VA 高级研究人员的指导。 在退伍军人管理局研究研讨会系列上两次展示她的新颖研究成果，并将继续寻求反馈 来自退伍军人事务部高级研究人员，包括她的退伍军人事务部导师——性类固醇合成失调和 分泌物是男性和女性不孕的主要原因，每 6 对夫妇就有 1 对不孕不育。 男性不育症是三分之一病例的主要因素，此外，不育症影响了大约 10% 的患者。 美国女性人口（610 万）；大约 100,000 名育龄女性退伍军人。 考虑到患有不孕症的男性和女性人数以及与不孕症相关的继发性影响 性类固醇生物合成失调了解调节 PKA 信号传导和动员的机制 类固醇生产底物具有对生殖健康和整体质量产生积极影响的巨大潜力 拟议的研究有望提供有关线粒体外作用的新信息。 通过线粒体 Dynamin-GTP 酶调节卵巢/睾丸类固醇合成和功能。 研究计划的重点是确定负责传输信号的分子机制 从外部环境到线粒体，引发线粒体结构和功能的变化，以及 然后将分子反应转化为类固醇生物合成的变化。拟议的目标测试整体。 线粒体 LH/PKA 调节影响线粒体结构、细胞器间的假设 沟通和最终类固醇生成将通过两个具体目标进行检验。 1：确定 S-OPA1 在类固醇生成中的作用 我们将检验 S-OPA1 作为 AKAP 的假设。 我们还将测试线粒体 PKA 信号传导是 LH 反应细胞中所必需的假设。 目标 2：确定 OMA1 和 S-OPA1 对 MICOS（线粒体接触位点）的作用。 和嵴组织系统）复杂和类固醇生成我们将检验 OMA1 和 S- 的假设。 OPA1 调节 IMM 内的线粒体 MICOS 复合物，这种调节对于最佳状态至关重要 为了测量这一点，我们将定义线粒体参数，包括 嵴组织、IMM 超复合物组装、线粒体能量学和线粒体核 我们预测线粒体中 MICOS 复合物的破坏将破坏线粒体。 这项研究支持我们完全实现长期目标。 了解控制性类固醇生成的机制 这项研究的短期目标。 我们的目标是发现 LH/PKA 信号传导如何诱导线粒体和胆固醇动员的变化，以达到最佳效果 黄体酮和睾酮的产生。