Mitochondrial Dynamics and Steroidogenesis

候选人-以下申请旨在启动Michele Plewes博士的研究生涯， 在退伍军人事务部爱荷华州内布拉斯加州医疗保健系统内，在退伍军人事务部高级医生约翰·戴维斯的指导下 研究职业科学家，在过去的30年里一直是备受尊敬的、退伍军人事务部资助的生殖内分泌学家。 普莱斯博士于2018年获得生物学博士学位，目前正在完成博士后培训，重点是 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-内布拉斯加大学医疗中心毗邻奥马哈退伍军人管理局医疗中心 已经建立了强有力的科学关系来完成拟议的研究。这项研究 环境是合作者和支持性的，有许多与其他研究合作的机会 科学家。具体来说，普莱斯博士将有机会讨论和展示她的工作，以获得关键的反馈 以及退伍军人事务部高级研究人员的指示。在她担任博士后助理期间，普莱斯博士曾被邀请 在退伍军人事务部研究研讨会系列上两次展示她的新研究成果，并将继续寻求反馈 来自退伍军人事务部的资深研究人员，包括她的退伍军人事务部导师。研究-性类固醇合成和性激素调节失调 分泌物是导致男性和女性不孕的主要原因。每6对夫妇中就有1对不孕不育， 在所有病例中，男性不育症是主要因素。此外，大约10%的人会受到不孕不育的影响 美国女性人口(610万)；大约10万名处于生育年龄的女性退伍军人。 考虑到患有不孕症和与之相关的继发性影响的男女人数 性激素生物发生的失调--了解调节PKA信号和动员的机制 生产类固醇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 生活的一部分。拟议的研究有望提供有关线粒体外所起作用的新信息。 线粒体动力蛋白-GTP酶对卵巢/睾丸类固醇合成和功能的调节这 研究计划的中心是识别负责传递信号的分子机制。 从外部环境到线粒体，启动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。提议的目标是对整体的考验 线粒体黄体生成素/蛋白激酶A调节影响线粒体结构、细胞器间的假说 沟通，最终类固醇的生成。核心假设将通过两个具体目标进行检验。目标 1：确定S-OPA1在类固醇合成中的作用。我们将检验S-OPA1作为AKAP的假设 对于黄体生成素反应细胞中的PKA。我们还将测试以下假设：线粒体PKA信号是 最佳类固醇合成。目的2：确定Oma1和S OPA1在线粒体接触位点上的作用 和脊骨组织系统)复合体和类固醇的发生。我们将检验Oma1和S的假设- OPA1调节IMM内的线粒体MICOS复合体，这种调节对于优化 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 脊骨组织、IMM超复合体组装、线粒体能量学和线粒体类核 安排好了。我们预测线粒体中MICOS复合体的破坏将破坏线粒体 并最终扰乱类固醇的合成。这项研究充分支持了我们的长期目标 了解控制性类固醇激素生成的机制。这项研究的短期目标是 是为了发现黄体生成素/蛋白激酶A信号如何引起线粒体的变化和胆固醇的最佳动员 孕酮和睾酮的产生。

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.