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: 10617348
• 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/10617348
• 关键词: Actins; Adherens Junction; Adhesiveness; Area; Biological Models; Biophysics; Cadherins; Caenorhabditis elegans; Cells; Complex; Congenital Abnormality; Cytoskeleton; Embryo; Embryonic Development; Epithelial Cells; Epithelium; Event; F-Actin; Genetic; Human; Human Development; Injury; Intercalated Cell; Invaded; LIM Domain; Malignant Neoplasms; Modeling; Morphogenesis; Movement; Organism; Pathway interactions; Polymers; Positioning Attribute; Process; Proteins; Regulation; Self-Injurious Behavior; Signal Pathway; Signal Transduction; Testing; Work; alpha catenin; cancer cell; cell motility; healing; human disease; in vivo; insight; 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 胚胎发育需要上皮片层的动态重塑， 在形态发生过程中自我转化了解这些事件具有重要的意义 来了解人类常见的先天缺陷和常见的癌症。我们的目标是 多学科，综合分析胚胎的形态发生运动， 详细的结构分析，单分子生物物理学，遗传学和动态体内分析， 利用C. elegans胚胎作为模型系统。我们最近的重点是两个广泛的领域 细胞骨架调节的机制：机械转导发生的机制， 上皮细胞形态发生过程中钙粘蛋白/连环蛋白复合物及其细胞机制 由基底外侧运动驱动的重排。我们将在这里继续这些重点： 1.定义形态发生过程中α-连环蛋白机械转导的机制：我们 将检查SRGP-1/srGAP与HMP-1/α-catenin的张力依赖性相互作用， SRGP-1募集如何正向调节钙粘蛋白复合物功能。 2.定义连接肌动蛋白网络在张力下的自愈机制， 形态发生：我们将测试一个模型，其中不同的含LIM结构域的重复 (LCR)蛋白质通过连接近端F-肌动蛋白网络稳定不同的亚结构 以防止自我伤害。 3.确定上皮细胞中局部肌动蛋白聚合的机制 重排：我们将使用综合方法来确定CRML-1/CARMIL 通过对倒刺末端肌动蛋白加帽机制的作用负调节运动性。 4.定义促进细胞极化运动的局部信号通路 重排：我们将确定额外的信号传导成分如何调节上皮细胞 细胞重排 作为这些研究的结果，我们将获得新的见解，了解粘附连接如何能够 承受并响应活有机体中的张力，我们将阐明一种新的途径， 通过基底外侧突起活性调节细胞嵌入。每个项目都有广泛的 对理解人类发育过程中各种细胞事件至关重要的过程的影响 发展和疾病。