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.

项目总结