PINCH-1 Interactions and Functions

PINCH-1 相互作用和功能

• 批准号: 7195461
• 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/7195461
• 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; Protein Overexpression; 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 therapeutics

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：细胞-细胞外基质（ECM）粘附和信号传导对于组织完整性和器官功能至关重要。它们调节多种过程，包括细胞骨架组织、细胞迁移和存活。细胞-ECM 粘附和信号传导的改变与人类疾病密切相关。这项竞争性延续申请的长期目标是确定细胞-ECM粘附和信号传导的分子基础，以及它们控制细胞行为和器官功能的机制。 PINCH-1 是细胞-ECM 粘附中广泛表达且进化保守的成分。最近的研究揭示了 PINCH-1 在调节肌动蛋白细胞骨架、细胞迁移和细胞凋亡中的重要作用。尽管最近取得了进展，但我们对 PINCH-1 功能的分子机制的理解仍然相当原始。此外，PINCH-1 在器官生物学中的作用仍然很大程度上未知。为了填补这些空白，我们提出了以下具体目标的研究。目标 1 是研究 PINCH-1 调节肌动蛋白细胞骨架和细胞迁移的机制。我们的假设是 PINCH-1 在肌动蛋白细胞骨架和细胞迁移的调节中发挥结构和信号传导作用。目的2是研究PINCH-1调节细胞凋亡的机制。我们将确定 PINCH-1 调节这一过程的结合伙伴和下游信号中间体。目标 3 是确定 PINCH-1 在肝脏生物学中的功能。我们将使用 Cre-lox 系统生成肝脏 PINCH-1 基因敲除小鼠。肝脏中 PINCH-1 表达消除的后果将通过分子、细胞、组织学和功能分析来确定。此外，我们将比较表型与消除肝脏中 ILK 诱导的表型。最后，我们将制备原代肝细胞并测试PINCH-1是否可以保护它们免受失巢凋亡（肝细胞移植的主要障碍）的影响。拟议的研究将揭示 PINCH-1（细胞-ECM 粘附的关键组成部分）的器官生物学和分子机制。此外，它们将帮助我们更好地理解细胞-ECM粘附介导的细胞骨架调节、细胞迁移和凋亡的一般机制。最终，这些研究可能会带来新的治疗方法来控制肝脏和其他器官中与异常细胞 ECM 粘附、迁移和凋亡相关的病理过程。