Structure and Function of Paxillin

Paxillin 的结构和功能

• 批准号: 10611918
• 负责人: Christopher E Turner
• 金额: $ 40.5万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611918
• 关键词: 3-Dimensional; Adaptor Signaling Protein; Animal Model; Apical; Biological Models; Breast Epithelial Cells; Cell Polarity; Cells; Cellular biology; Centrosome; Communication; Cytoskeletal Modeling; Cytoskeleton; Defect; Deposition; Development; Diabetes Mellitus; Disease; Disease Progression; Elements; Embryonic Development; Epithelium; Extracellular Matrix; F-Actin; Focal Adhesions; Funding; Goals; Golgi Apparatus; HDAC6 gene; Homeostasis; Intermediate Filaments; Intervention; Knockout Mice; Light; Malignant Neoplasms; Mediator; Mesenchymal; Microtubules; Molecular; Morphogenesis; Organoids; Play; Positioning Attribute; Process; Regulation; Research; Role; Scaffolding Protein; Signal Transduction; Structure; Time; Tissues; Vimentin; cell motility; developmental disease; imaging approach; knockout animal; migration; mouse model; novel; paxillin; polarized cell; programs; real-time images; superresolution imaging; trafficking

PROJECT SUMMARY The broad ongoing objective of this research program is to gain a deeper understanding of the fundamental mechanisms by which the focal adhesion adaptor/scaffold proteins paxillin and Hic-5 contribute to cell-matrix signaling and thereby control of cell polarity and migration in development and disease. Importantly, communication between the three elements of the cytoskeleton, the trafficking machinery and cell-matrix interactions is essential for establishing both apical-basal and front-rear migration polarity. However, our understanding of the key mechanisms coordinating and integrating these processes remains incomplete. Through our development of new paxillin and Hic-5 knock out mouse models, in combination with the use of various ex-vivo 1D, 2D and 3D cell matrix and organoid model systems and real time imaging approaches, we have identified new roles for paxillin in establishing epithelial and mesenchymal cell polarity, including regulation of centrosome and Golgi organization and microtubule stability via control of HDAC6 activity. We have also identified Hic-5 as a new mediator of F-actin-intermediate filament cross talk, mechanobiology and 3D extracellular matrix deposition and remodeling. Using these model systems in conjunction with quantitative real time confocal, light sheet and super resolution imaging approaches, the main goals that we will address in the upcoming funding period are- Goal 1: How does paxillin contribute to the regulation of polarized trafficking in directed mesenchymal cell migration? Goal 2: What is the role of paxillin in establishment of apical-basal polarity and in branching morphogenesis in mammary epithelial cells and Goal 3: How does Hic-5 regulate the vimentin intermediate filament cytoskeleton organization and function in motile cells and during epithelial-mesenchymal transition? Through the elucidation of these mechanisms we will be better positioned to develop rational approaches to disease intervention and to appreciate the basis of developmental disorders.

项目概要 该研究计划的广泛持续目标是更深入地了解 粘着斑适配器/支架蛋白桩蛋白和 Hic-5 的基本机制 有助于细胞基质信号传导，从而控制发育和发育过程中的细胞极性和迁移 疾病。重要的是，细胞骨架的三个要素之间的通讯，运输 机械和细胞-基质相互作用对于建立顶端-基底和前后部至关重要 迁移极性。然而，我们对协调和整合关键机制的理解 这些过程仍然不完整。通过我们开发新的桩蛋白和 Hic-5 敲除 小鼠模型，结合使用各种离体 1D、2D 和 3D 细胞基质和类器官 模型系统和实时成像方法，我们已经确定了桩蛋白的新作用 建立上皮细胞和间充质细胞极性，包括中心体和高尔基体的调节 通过控制 HDAC6 活性来调节组织和微管稳定性。我们还确定了 Hic-5 作为 F-肌动蛋白-中间丝串扰、力学生物学和 3D 细胞外基质的新介质 沉积和重塑。将这些模型系统与定量实时结合使用 共焦、光片和超分辨率成像方法，我们将在 即将到来的资助期是- 目标 1：paxillin 如何促进极化的调节 定向间充质细胞迁移的贩运？目标 2：桩蛋白在建立 乳腺上皮细胞的顶端-基底极性和分支形态发生以及目标 3：如何 Hic-5 调节运动细胞中波形蛋白中间丝细胞骨架的组织和功能 在上皮-间质转化期间？通过阐明这些机制，我们将 更好地制定疾病干预的合理方法并了解疾病干预的基础 发育障碍。