PINCH-1 Interactions and Functions

PINCH-1 相互作用和功能

• 批准号: 7329816
• 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/7329816
• 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

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 - 细胞基质（ECM）粘附和信号传导对于组织完整性和器官至关重要 功能。他们调节各种过程，包括细胞骨架组织，细胞迁移和 生存。细胞-ECM粘附和信号传导的改变与人类疾病密切相关。这 这种竞争连续应用的长期目标是确定分子基础基础细胞的基础 ECM粘附和信号传导以及它们控制细胞行为和器官功能的机制。 Pinch-1是细胞ECM粘附的广泛表达和进化保守的成分。最近的 研究表明，捏合1在调节肌动蛋白细胞骨架，细胞迁移和 凋亡。尽管最近取得了进展，但我们对捏合1的分子机制的理解 功能仍然非常原始。此外，Pinch-1在器官生物学中的作用在很大程度上未知。到 填补这些空白，我们提出了以下特定目的的研究。目标1是通过 捏合1调节肌动蛋白细胞骨架和细胞迁移。我们的假设是Pinch-1均扮演 结构和信号传导在调节肌动蛋白细胞骨架和细胞迁移中的作用。目标2是调查 捏-1调节细胞凋亡的机制。我们将确定约束伙伴和下游 信号传导中间体通过该中间体调节该过程。目标3是确定的功能 肝生物学中的捏合1。我们将使用Cre-Lox系统生成肝脏捏合1基因敲除小鼠。这 肝脏中捏合1表达消融的后果将通过分子，细胞， 组织学和功能分析。此外，我们将将表型与由 消除肝脏中的幼虫。最后，我们将准备初级肝细胞，并测试Pinch-1是否保护 它们来自Anoikis，这是肝细胞移植的主要障碍。 拟议的研究将阐明捏合1的器官生物学和分子机制，A 细胞-ECM粘附的关键成分。此外，他们将帮助我们更好地了解一般 控制细胞ECM粘附介导的细胞骨架调节，细胞迁移和凋亡的机制。 最终，这些研究可能导致新的治疗方法来控制病理过程 肝脏和其他与异常细胞ECM粘附，迁移和凋亡相关的器官。