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.

损伤后组织的不完全修复可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。圣诞老人实验室已经证明， ARF激活蛋白的细胞粘连素家族是体外HGF刺激的迁移和HGF刺激的迁移所必需的。 急性损伤后肾脏的恢复。迁移需要突起的协调， 在迁移细胞的前缘处的粘附和力产生。特异性细胞粘连素剪接变体 刺激整联蛋白粘附受体从再循环内体到细胞表面的运动。 类似地，Rac激活蛋白Dock180以一种类似的方式从再循环内体行进到细胞表面。 细胞粘连素依赖性方式响应HGF信号传导。本研究的目的是确定 和HGF刺激的迁移和组织修复中细胞粘连素依赖性运输的重要性。驱动 该项目的假设是HGF上调促迁移细胞粘连素的水平和活性 导致增强的细胞粘连素依赖性运输从而刺激组织迁移的变体 修复.这将通过三个具体目标进行测试：1）确定细胞粘连素信号传导在HGF中的作用。 2）确定HGF信号传导对细胞粘连素表达和剪接的影响;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。的 细胞粘连素信号在HGF刺激的修复途径和肾脏长期修复中的重要性 急性肾损伤后将确定。c-Met刺激信号通路调节 将测定响应于HGF的细胞粘连素mRNA的产生。细胞粘连素活性的影响 对附着力的形成，极化的振动信号和牵引力的产生， 将测定响应于HGF而迁移的细胞。从分子水平上理解 刺激迁移的HGF将为开发刺激组织愈合后的治疗提供框架 损害，并了解损害恢复的条件。促进伤口愈合的短期治疗 可能对伤害的长期健康影响产生深远影响。