PINCH-1 Interactions and Functions

细胞-细胞外基质(ECM)的黏附和信号传递对于组织的完整性和器官是必不可少的 功能。它们调节多种过程，包括细胞骨架组织、细胞迁移和 生死存亡。细胞-ECM黏附和信号的改变与人类疾病密切相关。这个 这一竞争性延续应用的长期目标是确定细胞- ECM黏附和信号，以及它们控制细胞行为和器官功能的机制。 PINCH-1是细胞-ECM黏附的一个广泛表达和进化保守的成分。近期 研究表明，PINCH-1在肌动蛋白细胞骨架的调节、细胞迁移和 细胞凋亡。尽管最近取得了进展，但我们对PINCH-1分子机制的理解 函数仍然非常原始。此外，PINCH-1在器官生物学中的作用在很大程度上仍不清楚。至 为了填补这些空白，我们建议进行以下具体目标的研究。目标1是通过以下方式来研究其机制 其中PINCH-1调控肌动蛋白细胞骨架和细胞迁移。我们的假设是，Pinch-1既扮演着 结构和信号在其对肌动蛋白细胞骨架和细胞迁移的调控中的作用。目标2是调查 PINCH-1调控细胞凋亡的机制。我们将确定有约束力的合作伙伴和下游 PINCH-1是调节这一过程的信号中间产物。目标3是确定 肝脏生物学中的PINCH-1。我们将使用Cre-lox系统产生肝脏收缩-1基因敲除小鼠。这个 消融肝脏中PINCH-1表达的后果将由分子，细胞， 组织学和功能分析。此外，我们将比较表型与那些诱导的 消除肝脏中的皱纹。最后，我们将准备原代肝细胞，并测试Pinch-1是否具有保护作用 它们来自失巢，这是肝细胞移植的主要障碍。 这些拟议的研究将有助于阐明Pinch-1的器官生物学和分子机制。 细胞-细胞外基质黏附的关键成分。此外，它们还将帮助我们更好地理解 细胞-细胞外基质黏附介导的细胞骨架调节、细胞迁移和细胞凋亡的机制。 最终，这些研究可能导致新的治疗方法，以控制病理过程 肝脏和其他器官与细胞-ECM的异常黏附、迁移和凋亡有关。

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.