ERO1 alpha in platelet activity and thrombosis

ERO1 α 在血小板活性和血栓形成中的作用

基本信息

  • 批准号:
    10621694
  • 负责人:
  • 金额:
    $ 43.6万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-02-10 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

Project Summary Despite advances in our understanding of the mechanisms mediating platelet thrombus formation, current antiplatelet drugs increase the risk of major bleeding. In an effort to identify novel therapeutic targets, we and others showed that intravascular protein disulfide isomerase (PDI) is crucial for full activation of αIIbβ3 integrin and platelet accumulation in arterial thrombosis, providing insights into a new antithrombotic agent. However, blocking the oxidoreductase activity of intravascular PDI prolongs tail bleeding times in mice. Our preliminary data have demonstrated that endoplasmic reticulum (ER) oxidoreductin 1α (Ero1α), a key oxidase of PDI in the ER, is released from activated platelets and that inhibition or deletion of platelet Ero1α alters the activity of platelet surface-bound PDI and impairs platelet aggregatory function. Furthermore, we have found that global deletion of Ero1α reduces the size of platelet thrombus formation without affecting initial platelet adhesion and tail bleeding times following vascular injury. Using biochemical, cellular and in vivo animal studies with novel pharmacological inhibitors and Ero1α conditional knockout and global knockout mice developed by our lab, we will test the hypothesis that platelet-released Ero1α regulates the function of PDI and αIIbβ3 integrin on the cell surface and contributes to the propagation step of platelet thrombus formation without affecting hemostasis following vascular injury. In Aim 1, we will identify the molecular mechanism by which extracellular Ero1α promotes platelet aggregation. In Aim 2, we will test whether arterial thrombotic conditions alter the function of extracellular Ero1α. In Aim 3, we will determine the pathophysiological role of intravascular and platelet-derived Ero1α in platelet adhesion and accumulation and vessel occlusion under thrombotic conditions. The proposed studies will identify a central regulatory mechanism of platelet thrombus formation and lead to the discovery of novel therapeutic strategies for the safe and effective treatment of thrombotic disease.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Jaehyung Cho其他文献

Jaehyung Cho的其他文献

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{{ truncateString('Jaehyung Cho', 18)}}的其他基金

Targeting LRRC8 signaling to prevent & treat arterial thrombosis in type 2 diabetes
针对 LRRC8 信号传导以防止
  • 批准号:
    10765748
  • 财政年份:
    2023
  • 资助金额:
    $ 43.6万
  • 项目类别:
ERO1 alpha in platelet activity and thrombosis
ERO1 α 在血小板活性和血栓形成中的作用
  • 批准号:
    10321687
  • 财政年份:
    2020
  • 资助金额:
    $ 43.6万
  • 项目类别:
Identification of an inhibitor of PDI-GPIbalpha signaling as a novel antithromboinflammatory agent
鉴定 PDI-GPIbalpha 信号传导抑制剂作为新型抗血栓炎症剂
  • 批准号:
    10253656
  • 财政年份:
    2020
  • 资助金额:
    $ 43.6万
  • 项目类别:
Identification of an inhibitor of PDI-GPIbalpha signaling as a novel antithromboinflammatory agent
鉴定 PDI-GPIbalpha 信号传导抑制剂作为新型抗血栓炎症剂
  • 批准号:
    10242945
  • 财政年份:
    2020
  • 资助金额:
    $ 43.6万
  • 项目类别:
ERO1 alpha in platelet activity and thrombosis
ERO1 α 在血小板活性和血栓形成中的作用
  • 批准号:
    10285785
  • 财政年份:
    2020
  • 资助金额:
    $ 43.6万
  • 项目类别:
Role of intravascular ERO1@ in acute lung injury
血管内ERO1@在急性肺损伤中的作用
  • 批准号:
    10686908
  • 财政年份:
    2020
  • 资助金额:
    $ 43.6万
  • 项目类别:
Role of intravascular ERO1@ in acute lung injury
血管内ERO1@在急性肺损伤中的作用
  • 批准号:
    10267181
  • 财政年份:
    2020
  • 资助金额:
    $ 43.6万
  • 项目类别:
Ero1α in platelet activity and thrombosis
Ero1α 在血小板活性和血栓形成中的作用
  • 批准号:
    9884277
  • 财政年份:
    2020
  • 资助金额:
    $ 43.6万
  • 项目类别:
Role of intravascular ERO1@ in acute lung injury
血管内ERO1@在急性肺损伤中的作用
  • 批准号:
    10469645
  • 财政年份:
    2020
  • 资助金额:
    $ 43.6万
  • 项目类别:
Role of intravascular ERO1@ in acute lung injury
血管内ERO1@在急性肺损伤中的作用
  • 批准号:
    10027023
  • 财政年份:
    2020
  • 资助金额:
    $ 43.6万
  • 项目类别:

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