ERK5 and CD36 link oxidative stress to platelet dysfunction and ischemic injury

ERK5 和 CD36 将氧化应激与血小板功能障碍和缺血性损伤联系起来

基本信息

  • 批准号:
    10323025
  • 负责人:
  • 金额:
    $ 63.2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-01-01 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

Risk of arterial thrombosis, including myocardial infarction (MI) and stroke, is increased in the setting of systemic disease states associated with chronic inflammation, including cancer, diabetes, atherosclerosis and obesity. Inappropriate platelet activation is a driving mechanism of thrombosis in these settings and recent studies suggest that mechanisms of platelet activation in diseased states may be different from those in normal healthy conditions. Dissecting these novel mechanisms is the central goal of this multi-PI proposal. Recent published and preliminary studies showed that endogenous danger signals well known to be generated during diseased states, including oxidized low density lipoprotein, advanced glycated proteins, cell-derived microparticles, and S100A peptides all interact with a specific platelet receptor, CD36, to initiate intracellular signals that promote platelet activation and thrombosis. Furthemore platelets were found to express the MAP kinase ERK5, a known sensor of reactive oxygen species (ROS). Platelet ERK5 was then shown to act as a redox switch responsive to extracellular ROS under ischemic conditions, promoting platelet activation and enhancing myocardial damage during MI; and ERK5 was found to be activated downstream of CD36 in response to oxLDL-mediated ROS generation. Platelet specific deletion of ERK5 ameliorated platelet activation and the pro-thrombotic state associated with hyperlipidemic oxidant stress. We thus hypothesize that ERK5 serves as a central “node” in pathologic platelet activation, responding to receptor-mediated intracellular signals triggered by CD36 and non- receptor mediated extracellular signals (ROS) mediated by tissue ischemia, through both its signaling and protein regulation activities. Specific aim 1 will test the hypothesis that specific ROS generated by CD36 signaling maintains platelets in a pro-activated state via activation of ERK5. Human In vitro and mouse in vivo studies will use genetic models, diet-induced disease models, and highly specific CD36 ligands to identify critical cell membrane partners necessary for CD36-mediated ERK5 activation, as well as downstream effectors of ROS and ERK5 in platelets; and to determine how ERK5 signaling integrates with “classic” pathways of platelet activation to promote thrombosis. Aim 2 will test the hypothesis that ERK5 regulates platelet protein expression by modulating platelet protein translation and/or protein ubiquitination. In vitro and in vivo models will be used to determine whether changes in platelet protein expression in response to ROS are dependent on protein synthesis, degradation, or both. Aim 3 will determine mechanisms by which platelet ERK5 activation in the setting of tissue ischemia and extracellular ROS increases tissue and organ dysfunction. Genetic and pharmacologic approaches and in vivo models of MI and oxidant stress will be used. By understanding mechanisms of platelet ERK5 activation and downstream pathways these studies will provide insights into `dysregulated' platelet function in pathologic conditions and ischemic environments that may lead to new therapeutic targets and better understanding of why current therapies based on platelet function in healthy conditions are inadequate.
动脉血栓形成的风险,包括心肌梗死(MI)和中风,增加了设置的全身性

项目成果

期刊论文数量(1)
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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CRAIG N MORRELL其他文献

CRAIG N MORRELL的其他文献

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{{ truncateString('CRAIG N MORRELL', 18)}}的其他基金

IMSD at the University of Rochester
罗彻斯特大学 IMSD
  • 批准号:
    10552964
  • 财政年份:
    2023
  • 资助金额:
    $ 63.2万
  • 项目类别:
Tissue Dependent Megakaryocyte Functions
组织依赖性巨核细胞功能
  • 批准号:
    10337469
  • 财政年份:
    2022
  • 资助金额:
    $ 63.2万
  • 项目类别:
Tissue Dependent Megakaryocyte Functions
组织依赖性巨核细胞功能
  • 批准号:
    10569096
  • 财政年份:
    2022
  • 资助金额:
    $ 63.2万
  • 项目类别:
Platelet-Regulated Immune Responses in Neonates Following Transfusion
新生儿输血后血小板调节的免疫反应
  • 批准号:
    10217253
  • 财政年份:
    2020
  • 资助金额:
    $ 63.2万
  • 项目类别:
Platelet-Regulated Immune Responses in Neonates Following Transfusion
新生儿输血后血小板调节的免疫反应
  • 批准号:
    10039184
  • 财政年份:
    2020
  • 资助金额:
    $ 63.2万
  • 项目类别:
Novel mechanisms of platelet modified monocyte phenotype
血小板修饰单核细胞表型的新机制
  • 批准号:
    10166903
  • 财政年份:
    2018
  • 资助金额:
    $ 63.2万
  • 项目类别:
Novel mechanisms of platelet modified monocyte phenotype
血小板修饰单核细胞表型的新机制
  • 批准号:
    10377113
  • 财政年份:
    2018
  • 资助金额:
    $ 63.2万
  • 项目类别:
Novel platelet functions for in T-cell helper cell responses
T 细胞辅助细胞反应中的血小板新功能
  • 批准号:
    9385749
  • 财政年份:
    2014
  • 资助金额:
    $ 63.2万
  • 项目类别:
Novel platelet functions for in T-cell helper cell responses
T 细胞辅助细胞反应中的血小板新功能
  • 批准号:
    8967578
  • 财政年份:
    2014
  • 资助金额:
    $ 63.2万
  • 项目类别:
Novel platelet functions for in T-cell helper cell responses
T 细胞辅助细胞反应中的血小板新功能
  • 批准号:
    8814885
  • 财政年份:
    2014
  • 资助金额:
    $ 63.2万
  • 项目类别:

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