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

• 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
• 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

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.

受伤后组织不完全修复会导致器官功能的纤维化和长期损害。适应不良 急性肾脏损伤后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受伤后的修复和恢复，包括肾脏， 肝，皮肤，肺和心脏。 HGF促进伤口愈合的一种机制是刺激 幸存的上皮细胞迁移并重新填充受损区域。 Santy实验室已经表明 HGF刺激的体外迁移和HGF刺激需要ARF激活蛋白的细胞粘着蛋白家族 急性受伤后肾脏恢复。迁移需要凸起的协调， 迁移细胞前缘的粘附和力产生。特定的细胞粘着蛋白剪接变体 刺激整联蛋白粘附受体从回收内体向细胞表面的运动。 同样，RAC激活的蛋白Dock180从回收内体传播到A中的细胞表面 响应于HGF信号传导的细胞粘着依赖性方式。这项研究的目的是确定角色 在HGF中依赖细胞粘着依赖性的迁移和组织修复的重要性。驾驶 该项目的假设是HGF上调了促迁移细胞蛋白的水平和活动 变体导致细胞粘着依赖性的运输增强，从而刺激组织中的迁移 维修。这将以三个特定目的进行测试：1）确定细胞粘着信号在HGF中的作用 刺激组织修复； 2）确定HGF信号传导对细胞粘着蛋白表达和剪接的影响；和 3）确定细胞粘着刺激的内吞回收在HGF刺激的迁移中的作用。这 在HGF刺激的修复途径和肾脏的长期修复中，细胞粘着信号传导的重要性 急性肾脏损伤后。 C-MET刺激了调节变化的信号通路 将确定细胞粘着蛋白mRNA对HGF的产生。细胞粘着活性的影响 在粘附形成时，在前缘的前沿两极分化的突出信号传导和牵引力产生 将确定根据HGF迁移的细胞。对通过 刺激迁移的HGF将提供一个框架来开发治疗以刺激组织后的愈合 损害并了解损害恢复的条件。一种促进伤口治疗的短期治疗 可能对伤害的长期健康影响产生深远的影响。