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

细胞粘附素依赖性回收在 HGF 刺激迁移和组织修复中的作用

基本信息

批准号：
10017071
负责人：
Lorraine C Santy
金额：
$ 10万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10017071
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Adhesions Aging Area Automobile Driving Basement membrane Cell surface Cells Chronic Kidney Failure Development Endosomes Epithelial Epithelial Cells Family Fibrosis Focal Adhesions Generations Genes Goals HGF gene Health Heart Impaired wound healing Impairment In Vitro Injury Integrins Kidney Kidney Failure Lead Liver Lung Messenger RNA Molecular Monomeric GTP-Binding Proteins Movement Mus Neoplasm Metastasis Normal tissue morphology Organ Pathologic Processes Pathway interactions Process Production Protein Family Proteins RNA Splicing Recovery Recycling Renal function Risk Factors Role Signal Pathway Signal Transduction Skin Structure Testing Tissues Total Internal Reflection Fluorescent Traction Traction Force Microscopy Travel Variant Work Wound Healing adhesion receptor arm cell motility healing injured kidney repair live cell imaging migration migration stimulating factor organ growth prevent receptor receptor recycling repaired response restoration therapy development tissue repair trafficking

项目摘要

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.

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可能导致慢性肾脏病的发展。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 促进伤口愈合的机制之一是通过刺激存活的上皮细胞迁移到受损区域并重新填充。 Santy 实验室表明 ARF 激活蛋白的细胞粘附素家族是 HGF 刺激的体外迁移和 HGF 刺激的迁移所必需的急性损伤后肾脏的恢复。迁移需要突出的协调，迁移细胞前缘的粘附和力产生。特定的细胞粘附素剪接变体刺激整合素粘附受体从循环内体到细胞表面的运动。类似地，Rac 激活蛋白 Dock180 以循环方式从内体循环到细胞表面。细胞粘附素依赖性方式响应 HGF 信号传导。本研究的目的是确定角色以及 HGF 中细胞粘附素依赖性运输刺激迁移和组织修复的重要性。驾驶该项目的假设是 HGF 上调促迁移细胞粘附素的水平和活性导致增强的细胞粘附素依赖性运输的变异，从而刺激组织过程中的迁移维修。这将通过三个具体目标进行测试：1) 确定细胞粘附素信号传导在 HGF 中的作用刺激组织修复； 2）确定HGF信号传导对细胞粘连蛋白表达和剪接的影响；和 3)确定细胞粘连素刺激的内吞再循环在HGF刺激的迁移中的作用。这细胞粘附素信号传导在 HGF 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才能确定。 c-Met 刺激信号通路调节变化将确定响应 HGF 的细胞粘连素 mRNA 的产生。细胞粘附素活性的影响粘附形成、极化突出信号和前缘牵引力的产生将确定响应 HGF 的细胞迁移。对所使用途径的分子理解刺激迁移的 HGF 将为开发刺激组织愈合的治疗方法提供框架损害并了解影响恢复的情况。促进伤口愈合的短期治疗可能会对伤害的长期健康影响产生深远的影响。