Roles of Hippo signaling and gap junctional communication in follicle development

以下申请旨在启动肯德拉博士的研究生涯。克拉克博士的指导下，约翰S。戴维斯克拉克博士于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，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。戴维斯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，弥合研究和应用医学之间的差距，窝藏基础和转化研究团队和医疗专业人员之间的合作努力。此外，UNMC毗邻奥马哈VA医疗中心，距离内布拉斯加大学林肯分校不到40分钟。在UNMC，VA和UNL的环境提供了大量的合作和研究的机会。研究-卵巢产生女性卵子，卵母细胞和激素，这对生殖和生活质量至关重要。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，雅普是Hippo通路的主要成分，在卵巢中起着重要作用。卵泡的形成和成熟是一个依赖于间隙连接形成的细胞过渡过程，间隙连接允许小分子在细胞之间通过。Hippo通路在早期卵泡发育中的作用及其与细胞间隙连接通讯（GJIC）的关系尚不清楚。该方案中的实验旨在检验以下假设：（1）体细胞中雅普的激活刺激卵泡发育的早期阶段，以及（2）雅普的改变对发育中卵泡中的GJIC产生不利影响。在这个提议中，我们将利用一个易于处理的体内小鼠模型来研究卵泡发育和一个转基因小鼠模型结合先进的显微镜技术来测量细胞之间的通信。本研究的目标是发现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。我目前的研究目标是确定Hippo通路在早期卵泡发育中的作用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的研究人员，专注于环境诱导的生殖失败的分子机制。

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.