Regulation of dynamic actin networks during epithelial morphogenesis

上皮形态发生过程中动态肌动蛋白网络的调节

• 批准号: 10406751
• 负责人: Jeffrey D Hardin
• 金额: $ 55.57万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-13 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406751
• 关键词: Actins; Adherens Junction; Adhesiveness; Area; Biological Models; Biophysics; Cadherins; Caenorhabditis elegans; Cells; Complex; Congenital Abnormality; Embryo; Embryonic Development; Epithelial; Epithelial Cells; Event; F-Actin; Genetic; Human; Human Development; Injury; Invaded; LIM Domain; Malignant Neoplasms; Modeling; Morphogenesis; Movement; Organism; Pathway interactions; Positioning Attribute; Process; Proteins; Regulation; Self-Injurious Behavior; Signal Pathway; Signal Transduction; Testing; Work; alpha Actin; alpha catenin; cancer cell; cell motility; healing; human disease; in vivo; insight; intercalation; mechanotransduction; multidisciplinary; novel; polymerization; prevent; recruit; single molecule

Project Summary Embryonic development requires the dynamic remodeling of epithelial sheets as the embryo transforms itself during morphogenesis. Understanding these events has important implications for understanding common human birth defects and common cancers. Our aim is a multidisciplinary, integrated analysis of morphogenetic movements in embryos that unites detailed structural analysis, single-molecule biophysics, genetics, and dynamic in vivo analysis, using the C. elegans embryo as a model system. Our recent focus has been in two broad areas of cytoskeletal regulation: the mechanisms by which mechanotransduction occurs through the cadherin/catenin complex during morphogenesis, and cellular mechanisms of epithelial cell rearrangement driven by basolateral motility. We will continue these emphases here: 1. Define mechanisms of α-catenin mechanotransduction during morphogenesis: We will examine the tension-dependent interaction of SRGP-1/srGAP with HMP-1/α-catenin and how SRGP-1 recruitment positively modulates cadherin complex function. 2. Define mechanisms of self-healing of junctional actin networks under tension during morphogenesis: We will test a model in which different LIM-domain containing repeat (LCR) proteins stabilize different substructures with the junctional proximal F-actin network under tension to prevent self-injury. 3. Define mechanisms of local actin polymerization in during epithelial cell rearrangement: We will use an integrated approach to determine how CRML-1/CARMIL negatively regulates motility via effects on the barbed end actin capping machinery. 4. Define local signaling pathways that promote polarized motility during cell rearrangement: We will determine how additional signaling components regulate epithelial cell rearrangement. As a result of these studies, we will gain new insight into how adherens junctions are able to withstand and respond to tension in a living organism, and we will elucidate a novel pathway regulating cell intercalation via basolateral protrusive activity. Each project has widespread implications for understanding processes crucial for diverse cellular events during human development and disease.

项目摘要 胚胎发育需要将上皮片作为胚胎进行动态重塑 在形态发生过程中改变自身。了解这些事件具有重要的含义 理解常见的人类出生缺陷和常见癌症。我们的目标是 对单位的胚胎中形态发生运动的多学科，综合分析 详细的结构分析，单分子生物物理学，遗传学和体内动态分析， 使用秀丽隐杆线虫胚作为模型系统。我们最近的重点是两个广泛的领域 细胞骨架调节：通过 cadherin/catenin复合物在形态发生过程中和上皮细胞的细胞机制 重排由大体运动驱动。我们将在这里继续这些重点： 1。定义形态发生过程中α-catenin机械转导的机制：我们 将检查SRGP-1/SRGAP与HMP-1/α-catenin和 SRGP-1募集如何阳性调节钙粘蛋白复合物功能。 2。定义连接肌动蛋白网络在紧张期间的自我修复机制 形态发生：我们将测试一个模型，其中不同的lim域包含重复 （LCR）蛋白质通过连接代理F-肌动蛋白网络稳定不同的子结构 在紧张局势下防止自我伤害。 3。定义上皮细胞中局部肌动蛋白聚合的机制 重排：我们将使用一种集成的方法来确定CRML-1/Carmil的方式 通过对带刺端肌动蛋白封盖机械的影响进行负调节运动。 4。定义局部信号通路，以促进细胞期间的极化运动 重排：我们将确定其他信号分量如何调节上皮 细胞重排。 由于这些研究，我们将获得有关粘附连接能力如何的新见解 应承受并应对活生物体的张力，我们将阐明一种新颖的途径 通过基底外侧突出活性调节细胞插入。每个项目都有宽度 了解人类期间对多元化细胞事件至关重要的过程的意义 发展与疾病。