The role of Cytohesin dependent recycling in HGF stimulated migration and tissue repair

损伤后组织的不完全修复会导致纤维化和器官功能的长期损害。适应不良 急性肾损伤后的修复会导致慢性肾脏疾病的发展。 肝细胞生长因子促进许多组织损伤后的修复和恢复，包括肾脏， 肝脏、皮肤、肺和心脏。HGF促进伤口愈合的一种机制是通过刺激 存活的上皮细胞迁移到受损区域并重新填充。桑蒂实验室已经证明 肝细胞生长因子刺激的体外迁移和肝细胞生长因子刺激的迁移需要ARF激活蛋白的细胞粘附素家族 急性损伤后肾脏的恢复。迁移需要协调突起， 迁移细胞前沿的黏附和作用力。特异性细胞粘附素剪接变异体 刺激整合素黏附受体从循环内小体到细胞表面的运动。 类似地，RAC激活蛋白Dock180从回收内小体到细胞表面 HGF信号转导以细胞内酯依赖的方式应答。这项研究的目的是确定 细胞粘附素依赖的运输在肝细胞生长因子刺激迁移和组织修复中的重要性。驾驶 该项目的假设是，HGF上调亲迁移细胞粘附素的水平和活性 导致细胞粘附素依赖转运增强的变体，从而刺激组织中的迁移 修理。这将以三个特定的目的进行测试：1)确定细胞粘素信号在肝细胞生长因子中的作用 刺激组织修复；2)确定HGF信号对细胞粘附素表达和剪接的影响；以及 3)确定细胞粘附素刺激的细胞内循环在HGF刺激的迁移中的作用。这个 细胞粘素信号在肝细胞生长因子刺激的修复途径和肾脏长期修复中的重要性 急性肾损伤后将被确定。C-Met激活的信号通路调节细胞周期的变化 对HGF的反应产生的细胞粘素mRNAs将被确定。细胞粘附素活性的影响 关于黏附形成、极化突起信号和前缘牵引力的产生 细胞对HGF的反应将被确定为迁移。从分子水平上理解基因所使用的途径 HGF刺激迁移将提供一个框架，以开发刺激组织后愈合的治疗方法 了解损害和了解损害恢复的条件。一种促进伤口愈合的短期治疗方法 可能对伤害的长期健康影响产生深远影响。

Incomplete repair of tissues after injury can lead to fibrosis and long-term impairment of organ function. Maladaptive repair after Acute Kidney Injury can lead to the development of Chronic Kidney Disease. Hepatocyte Growth Factor promotes repair and recovery after injury in a number of tissues, including kidney, liver, skin, lung and heart. One mechanism by which HGF promotes wound healing is by stimulating surviving epithelial cells to migrate into and repopulate the damaged regions. The Santy lab has shown that cytohesin family of ARF-activating proteins is required for HGF-stimulated migration in vitro and HGF-stimulated recovery of the kidney after acute injury. Migration requires the coordination of protrusion, adhesion and force generation at the leading edge of migrating cells. Specific cytohesin splice variants stimulate the movement of integrin adhesion receptors from recycling endosomes to the cell surface. Similarly, the Rac-activating protein Dock180 travels from recycling endosomes to the cell surface in a cytohesin-dependent manner in response to HGF signaling. The objective of this study is to determine the role and importance of cytohesin dependent trafficking in HGF stimulated migration and tissue repair. The driving hypothesis of the project is that HGF upregulates both the level and activity of pro-migratory cytohesin variants leading to enhanced cytohesin-dependent trafficking thereby stimulating migration during tissue repair. This will be tested with three specific aims: 1) Determine the role of cytohesin signaling in HGF stimulated tissue repair; 2) Determine the impact of HGF signaling on cytohesin expression and splicing; and 3) Determine the role of cytohesin stimulated endocytic recycling in HGF-stimulated migration. The importance of cytohesin signaling in HGF-stimulated repair pathways and on long-term repair of the kidney after acute kidney injury will be determined. The c-Met stimulated signaling pathways regulating changes in the production of cytohesin mRNAs in response to HGF will be determined. The impact of cytohesin activity on adhesion formation, polarized protrusive signaling and traction force generation at the leading edge of cells migrating in response to HGF will be determined. A molecular understanding of the pathways used by HGF to stimulate migration will provide a framework to develop treatments to stimulate healing after tissue damage and to understand conditions that impair recovery. A short-term treatment that promotes wound-healing could have profound impacts on the long-term health impacts of injury.