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Role of LH-induced cell migration and cofilin dephosphorylation in ovulation

LH 诱导的细胞迁移和丝动蛋白去磷酸化在排卵中的作用

基本信息

批准号：
10593888
负责人：
Corie Marie Owen
金额：
$ 4.19万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10593888
关键词：
Actins Antibodies Apical Basal lamina Biological Assay Blood Vessels Cell Count Cell Migration Induction Cell Shape Cells Clinical Treatment Complex Cytoskeleton Disease Dominant-Negative Mutation Event Female infertility Fertility Gene Expression Glutamates Hemagglutinin Hour Image Immune Knowledge LH Receptors Label Luteal Cells Luteinizing Hormone Mediator Meiosis Methods Movement Mus Oocytes Ovary Ovulation Peptide Hydrolases Phosphorylation Physiologic pulse Post-Translational Protein Processing Pregnancy Protein Dephosphorylation Proteins Receptor Signaling Regulation Research Proposals Role Rupture Serine Signal Transduction Site Surface Testing Time Tissues Visualization Woman actin depolymerizing proteins cell motility cell type cofilin corpus luteum directional cell female fertility granulosa cell hormonal signals improved in vivo insight migration novel prevent receptor receptor expression response theca cell two photon microscopy

项目摘要

Project Abstract: In the ovary, luteinizing hormone (LH) signals through the luteinizing hormone receptor (LHR) to initiate the transition from preovulatory follicle to corpus luteum. Essential to this transition are the movement of the oocyte to the site of ovulation, basal lamina breakdown, and reorganization of the granulosa cells to form the corpus luteum. LHR-expressing cells migrate inwards in response to LH and at later time points after LH stimulation, the basal lamina is pulled inwards in regions of high HA-LHR expression. These results have led to the hypothesis that LH-induced granulosa cell migration aids in regulating the transition from preovulatory follicle to corpus luteum. Previous studies in isolated granulosa cells have indicated that LH signaling disrupts actin to allow cytoskeletal rearrangement and induces granulosa cell motility. One potential mediator of these actions is cofilin, an actin-depolymerizing protein. Cofilin activity is required for directional cell motility in multiple cell types, and expression of a dominant-negative form of the protein in granulosa cell inhibits LH-induced actin reorganization. However, the role of cofilin dephosphorylation in vivo has yet to be investigated. This project investigates the hypothesis that LH induces cell migration through dephosphorylation of cofilin, and that the migration pulls the basal lamina inward to aid in rupture during ovulation and reorganizes the cells to begin corpus luteum formation. In aim 1, live-tissue confocal and two-photon microscopy will be used to analyze granulosa cell migration in intact follicles and determine how granulosa cell migration contributes to basal lamina invaginations and ovulation. In aim two, a novel mouse line that expresses a dominant-negative form of cofilin will be used to explore the hypothesis that cofilin dephosphorylation regulates granulosa cell migration. These studies will provide novel information about the regulation of ovulation and could lead to clinical treatments for anovulatory diseases.

项目摘要：在卵巢中，促黄体生成激素（LH）通过促黄体生成激素受体（LHR）发出信号，启动从排卵前卵泡到黄体的转变。这种转变的关键是卵母细胞的运动到排卵部位，基底层破裂，颗粒细胞重组形成小体黄体表达LHR的细胞响应LH向内迁移，并且在LH刺激后的稍后时间点，在HA-LHR高表达的区域，基底层被向内拉。这些结果导致了 LH诱导的颗粒细胞迁移有助于调节排卵前卵泡向排卵后卵泡的转变，黄体先前在分离的颗粒细胞中的研究表明LH信号传导破坏肌动蛋白，允许细胞骨架重排并诱导颗粒细胞运动。这些行动的一个潜在调解人是 cofilin，一种肌动蛋白解聚蛋白。切丝蛋白活性是多种细胞类型中定向细胞运动所必需的，颗粒细胞中显性负性表达的蛋白质抑制LH诱导的肌动蛋白重组。然而，cofilin去磷酸化在体内的作用还有待研究。这个项目研究了LH通过cofilin的去磷酸化诱导细胞迁移的假设，在排卵期间，迁移将基底膜向内拉以帮助破裂，并重组细胞以开始黄体形成。在aim 1中，活组织共聚焦和双光子显微镜将用于分析完整卵泡中颗粒细胞迁移，并确定颗粒细胞迁移如何促进基底层内陷和排卵。在目标二中，一种表达cofilin显性负性形式的新型小鼠品系将被用来探讨cofilin去磷酸化调节颗粒细胞迁移的假设。这些研究将提供有关排卵调节的新信息，并可能导致临床治疗，无排卵性疾病