PINCH-1 Interactions and Functions

PINCH-1 相互作用和功能

• 批准号: 7534806
• 负责人: CHUANYUE WU
• 金额: $ 28.09万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7534806
• 关键词: Ablation; Abnormal Cell; Actins; Adhesions; Anoikis; Apoptosis; Binding; Biological Models; Biology; Catalytic Domain; Cells; Cellular Structures; Complex; Cytoskeletal Modeling; Cytoskeletal Proteins; Cytoskeleton; Defect; Extracellular Matrix; Funding; Goals; Hepatocyte; Integrins; Knockout Mice; LIM Domain Protein; Lead; Light; Liver; MAPK8 gene; Mediating; Molecular; Molecular Biology; Mus; Organ; Pathologic Processes; Phenotype; Play; Process; Protein Binding Domain; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; System; Testing; Tissues; Transplantation; Tumor Suppressor Proteins; base; cell behavior; cell motility; design; fascinate; human disease; integrin-linked kinase; migration; novel therapeutic intervention; overexpression

Cell-extracellular matrix (ECM) adhesion and signaling are essential for tissue integrity and organ functions. They regulate a variety of processes including cytoskeletal organization, cell migration and survival. Alterations of cell-ECM adhesion and signaling are intimately associated with human diseases. The long-term goal of this competing continuation application is to determine the molecular basis underlying cell- ECM adhesion and signaling, and the mechanism whereby they control cell behavior and organ function. PINCH-1 is a widely expressed and evolutionally conserved component of cell-ECM adhesions. Recent studies have revealed important roles of PINCH-1 in regulation of actin cytoskeleton, cell migration and apoptosis. Despite recent progress, our understanding of the molecular mechanisms by which PINCH-1 functions is still quite primitive. Furthermore, the roles of PINCH-1 in organ biology remain largely unknown. To fill these gaps, we propose studies with the following specific aims. Aim 1 is to investigate the mechanisms by which PINCH-1 regulates actin cytoskeleton and cell migration. Our hypothesis is that PINCH-1 plays both a structural and a signaling role in its regulation of actin cytoskeleton and cell migration. Aim 2 is to investigate the mechanism by which PINCH-1 regulates apoptosis. We will identify the binding partners and downstream signaling intermediates through which PINCH-1 regulates this process. Aim 3 is to determine the functions of PINCH-1 in liver biology. We will generate liver PINCH-1 knockout mice using the Cre-lox system. The consequences of ablation of PINCH-1 expression in the liver will be determined by molecular, cellular, histological and functional analyses. Furthermore, we will compare the phenotypes with those induced by elimination of ILK in the liver. Finally, we will prepare primary hepatocytes and test whether PINCH-1 protects them from anoikis, a major obstacle for hepatocyte transplantation. The proposed studies will shed light on the organ biology and molecular mechanism of PINCH-1, a key component of cell-ECM adhesions. Furthermore, they will help us to better understand the general mechanism governing cell-ECM adhesion-mediated cytoskeletal regulation, cell migration and apoptosis. Ultimately, these studies may lead to novel therapeutic approaches to control pathological processes in the liver and other organs that are associated with abnormal cell-ECM adhesion, migration and apoptosis.

细胞-细胞外基质（ECM）的粘附和信号传导对组织完整性和器官至关重要