PINCH-1 Interactions and Functions

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完整性至关重要。 功能协调发展的它们调节多种过程，包括细胞骨架组织、细胞迁移和细胞增殖。 生存细胞-ECM粘附和信号传导的改变与人类疾病密切相关。的 这种竞争性继续申请的长期目标是确定细胞的分子基础， 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组分。最近 研究已经揭示了PINCH-1在调节肌动蛋白细胞骨架、细胞迁移和 凋亡尽管最近的进展，我们的理解的分子机制，PINCH-1 功能仍然很原始。此外，PINCH-1在器官生物学中的作用在很大程度上仍然未知。到 为了填补这些空白，我们建议开展具有以下具体目标的研究。目的1是探讨机制， PINCH-1调节肌动蛋白细胞骨架和细胞迁移。我们的假设是，PINCH-1既起作用， 在调节肌动蛋白细胞骨架和细胞迁移中具有结构和信号作用。目标2：调查 PINCH-1调节细胞凋亡的机制。我们将确定结合伙伴和下游 PINCH-1通过其调节该过程的信号传导中间体。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PINCH-1敲除小鼠。的 肝脏中PINCH-1表达的消除的结果将由分子，细胞， 组织学和功能分析。此外，我们将比较表型与诱导的表型。 消除肝脏中的ILK。最后，我们将制备原代肝细胞，并测试PINCH-1是否能保护 他们从失巢凋亡，肝细胞移植的主要障碍。 这些研究将有助于阐明PINCH-1的器官生物学和分子机制， 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，这些研究可能会导致新的治疗方法来控制病理过程中， 肝脏和其他器官与异常细胞-ECM粘附、迁移和凋亡相关。

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.