Roles of Hippo signaling and gap junctional communication in follicle development

Hippo 信号传导和间隙连接通讯在卵泡发育中的作用

基本信息

批准号：
10530588
负责人：
Kendra L Clark
金额：
$ 6.76万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10530588
关键词：
Adult Affect Antral Apoptosis Appearance Architecture Basic Science Biological Assay Caliber Cattle Cell Communication Cell Nucleus Cell Proliferation Cells Cellular Morphology Cessation of life Collaborations Communication Connexins Data Development Doctor of Philosophy Embryonic Development Endocrine Environment Event Failure Fellowship Female Funding Gap Junctions Gene Expression Genetic Genomics Germ Cells Goals Gonadotropins Green Fluorescent Proteins Growth Health Homeostasis Hormones Human Infertility Knowledge Lead Lentivirus Life Liquid substance Maintenance Malignant neoplasm of ovary Measures Medical Medical center Medicine Menarche Menopause Mentorship Metabolic Pathway Microscopy Molecular Morphology Mus Nebraska Neoplasms Nutrient Oocytes Organ Organ Size Outcome Ovarian Ovarian Diseases Ovarian Follicle Ovary Ovulation Pathologic Pathway interactions Periodicity Physiological Play Polycystic Ovary Syndrome Process Proliferating Quality of life Regulation Reproduction Reproductive Health Research Research Personnel Role Signal Pathway Signal Transduction Somatic Cell Structure Techniques Testing Tissue Recombination Tissues Training Transgenic Mice Translational Research Translations United States Department of Agriculture United States National Institutes of Health Universities Woman career cell growth design egg experience experimental study fetal folliculogenesis granulosa cell hormone regulation improved in vivo intercellular communication knock-down mouse model oocyte maturation post-doctoral training primary ovarian insufficiency protein expression reproductive reproductive system disorder response self-renewal small hairpin RNA small molecule spatiotemporal stem cell self renewal

项目摘要

The following application is intended to initiate the research career of Dr. Kendra L. Clark under the mentorship of Dr. John S. Davis. Dr. Clark received her PhD in Genetics and Genomics in December 2019 and is currently completing her postdoctoral training focused exclusively on reproductive health research, specifically in regulation of early follicle development and cellular communication. Dr. Davis is an outstanding reproductive biologist, has had extensive experience in training researchers at various levels, and has been funded through the NIH, USDA, and VA for the past 30 years. Environment - The University of Nebraska Medical Center (UNMC) is a leading academic health and research center that bridges the gap between research and applied medicine, harboring collaborative efforts between basic and translational research teams and medical professionals. Further, UNMC is adjacent to the Omaha VA Medical Center and within 40 minutes of University of Nebraska - Lincoln. The environment at UNMC, the VA, and UNL provides abundant opportunity for collaboration and research. Research - The ovary produces the female egg, the oocyte, and hormones which are critical for reproduction and quality-of-life. The Hippo signaling pathway controls organ size by regulating cell growth, death, and self-renewal. Recent studies demonstrate that YAP, a main component of the Hippo pathway, plays an important role in the ovary. The formation and maturation of follicles is a cellular transition process dependent on the formation of gap junctions, connections that allow passage of small molecules between cells. There is a lack of knowledge in the contribution of the Hippo pathway in early follicle development and the relationship with gap junction intercellular communication (GJIC). Experiments in this proposal are designed to test the hypothesis that (1) activation of Yap in somatic cells stimulates the early stages of follicle development and (2) alterations in Yap adversely impacts GJIC in the developing follicle. In this proposal we will utilize a tractable in vivo mouse model to study follicle development and a transgenic mouse model combined with advanced microscopy techniques to measure communication between cells. The goal of this research is to discover how Hippo signaling events and the interactions with cellular junctions in the follicle contribute to follicle development and oocyte growth. Outcomes for Fellowship Training - My current research objectives are to determine the contribution of the Hippo pathway in early follicular development and the relationship with gap junction intercellular communication (GJIC). My long-term research goal is to develop into an independent researcher with a focus on the molecular mechanisms responsible for environmentally-induced reproductive failure.

以下申请旨在启动 Kendra L. Clark 博士在 John S. Davis 博士的指导下的研究生涯。克拉克博士于 2019 年 12 月获得遗传学和基因组学博士学位，目前正在完成她的博士后培训，该培训专注于生殖健康研究，特别是早期卵泡发育和细胞通讯的调节。 Davis博士是一位杰出的生殖生物学家，在培训各级研究人员方面拥有丰富的经验，并在过去30年中获得了NIH、USDA和VA的资助。环境 - 内布拉斯加大学医学中心 (UNMC) 是一个领先的学术健康和研究中心，它弥合了研究和应用医学之间的差距，为基础和转化研究团队以及医疗专业人员之间的合作提供了平台。此外，UNMC 毗邻奥马哈退伍军人医疗中心，距离内布拉斯加大学林肯分校不到 40 分钟路程。 UNMC、VA 和 UNL 的环境为合作和研究提供了丰富的机会。研究——卵巢产生雌性卵子、卵母细胞和对生殖和生活质量至关重要的激素。 Hippo 信号通路通过调节细胞生长、死亡和自我更新来控制器官大小。最近的研究表明，YAP 作为 Hippo 通路的主要成分，在卵巢中发挥着重要作用。卵泡的形成和成熟是一个细胞转变过程，依赖于间隙连接的形成，间隙连接允许小分子在细胞之间通过。目前对于 Hippo 通路在早期卵泡发育中的贡献以及与间隙连接细胞间通讯 (GJIC) 的关系缺乏了解。本提案中的实验旨在检验以下假设：(1) 体细胞中 Yap 的激活刺激卵泡发育的早期阶段，(2) Yap 的改变会对发育中的卵泡中的 GJIC 产生不利影响。在本提案中，我们将利用易于处理的体内小鼠模型来研究卵泡发育，并利用转基因小鼠模型与先进的显微镜技术相结合来测量细胞之间的通讯。这项研究的目的是发现 Hippo 信号事件以及与卵泡中细胞连接的相互作用如何促进卵泡发育和卵母细胞生长。奖学金培训的成果 - 我目前的研究目标是确定 Hippo 通路在早期卵泡发育中的贡献以及与间隙连接细胞间通讯 (GJIC) 的关系。我的长期研究目标是发展成为一名独立研究员，重点研究环境引起的生殖障碍的分子机制。