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

基本信息

  • 批准号:
    10242945
  • 负责人:
  • 金额:
    $ 55.13万
  • 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:
    2020-09-04 至 2023-07-31
  • 项目状态:
    已结题

项目摘要

Project Summary Thromboinflammatory diseases, including atherothrombosis, stroke and peripheral vasculitis, result in >30% of all deaths globally. Underlying the pathology of thromboinflammation is increased adhesiveness of platelets and leukocytes. Although many antiplatelet and anti-inflammatory therapies have been used for disease treatment, these drugs increase the risk of major bleeding or impair immune responses. Using protein disulfide isomerase (PDI) conditional knockout (CKO) mice and inhibitors, we and others have shown that extracellular PDI is crucial for platelet thrombus formation in arterial thrombosis and neutrophil recruitment to inflamed endothelium in vascular inflammation. However, inhibition of extracellular PDI with a function-blocking antibody prolongs tail bleeding times in mice, raising a concern that specific inhibition of PDI may perturb hemostatic function. Our recent studies have demonstrated that platelet-released PDI promotes the ligand-binding function of glycoprotein Ibα (GPIbα) and enhances GPIbα-mediated platelet adhesiveness, platelet-neutrophil aggregation and vascular occlusion under thromboinflammatory conditions. These results suggest that inhibitors blocking the PDI-GPIbα signaling axis may be a novel antithromboinflammatory drug. Using high throughput screening, we have identified one compound that specifically inhibits PDI-GPIbα binding and GPIbα-mediated platelet aggregation. We have found that iv injection of the compound into mice abolishes platelet-neutrophil interactions and improves blood flow rates in microvessels under thromboinflammatory conditions. Unlike a conventional inhibitor of PDI or GPIbα, treatment with our compound does not prolong tail bleeding times in mice. These results have provided evidence for the feasibility of identifying small-molecule inhibitors targeting a specific PDI signaling pathway. In Aim 1, using the computer-aided drug design technique and a series of in vitro studies, we will identify small- molecule compounds that specifically block PDI-GPIbα signaling and GPIbα-mediated platelet functions. In Aim 2, we will synthesize derivatives of hits, test them in animal studies and examine DMPK profiles of the selected compounds. The proposed study will prove that compared to conventional inhibition of PDI or GPIbα, specific inhibition of the PDI-GPIbα signaling axis might be a safer and effective therapeutic strategy for treating thromboinflammatory 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:
    $ 55.13万
  • 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:
    $ 55.13万
  • 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:
    $ 55.13万
  • 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:
    $ 55.13万
  • 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:
    $ 55.13万
  • 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:
    $ 55.13万
  • 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:
    $ 55.13万
  • 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:
    $ 55.13万
  • 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:
    $ 55.13万
  • 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:
    10621694
  • 财政年份:
    2020
  • 资助金额:
    $ 55.13万
  • 项目类别:

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