Integrin activation during neutrophil adhesion and vascular inflammation

中性粒细胞粘附和血管炎症期间的整合素激活

基本信息

  • 批准号:
    10822018
  • 负责人:
  • 金额:
    $ 21.3万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-01-01 至 2024-03-04
  • 项目状态:
    已结题

项目摘要

Neutrophils, which are essential for host defense against bacterial and fungal infections, induce inflammation following tissue necrosis or ischemic injury. If not properly resolved, neutrophilic inflammation is the driving force behind a plethora of human inflammatory diseases. Neutrophils arrive at the site of injury from the bloodstream by first rolling and then arresting. Arrest is triggered by chemokines that induce the high-affinity conformation of ..2 integrins. Two FERM domain proteins, kindlin-3 and talin-1, are required for neutrophil arrest. It is well known that talin-1, an adaptor protein that binds the actin cytoskeleton, activates integrins by binding and altering the topology of the .. transmembrane domain. We recently reported that kindlin-3 is recruited to the plasma membrane through its pleckstrin homology domain prior to neutrophil arrest. However, the mechanism underlying neutrophil spreading and the role of kindlin-3 in this process are poorly understood. Moreover, how kindlin-3 cooperates with talin-1 to activate integrins and whether kindlin-3 also functions as an adaptor protein by directly binding to actin are completely unknown. Our overarching hypothesis is that, during neutrophil spreading, both kindlin-3 and talin-1 are simultaneously recruited to the plasma membrane, where kindlin-3 organizes high-affinity integrin activation. To test this hypothesis, we generated reporter mouse lines for simultaneous detection of ..2 integrin activation and imaging of kindlin-3 and talin-1 in mouse neutrophils. In Aim 1, we will test the hypothesis that kindlin-3 organizes a ring of clustered high-affinity ..2 integrins during neutrophil spreading under flow conditions; in Aim 2, we will test the hypothesis that kindlin-3 regulates integrin activation by directly binding to the actin cytoskeleton; and in Aim 3, we will determine the role of ..2 integrin activation in ischemia-reperfusion injury (IRI). The proposed research is conceptually innovative and highly significant because it will resolve the enigma of how kindlin-3 organizes high-affinity integrin activation and define the role it plays in IRI-induced inflammation. Successful completion of this proposal will establish molecular mechanisms of integrin activation and provide mechanistic insight into neutrophil spreading and vascular inflammation.
中性粒细胞是宿主抵御细菌和真菌感染所必需的

项目成果

期刊论文数量(0)
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