Regulation of thrombin-induced p38 MAPK pro-inflammatory signaling by deubiquitinases

去泛素酶对凝血酶诱导的 p38 MAPK 促炎信号的调节

基本信息

  • 批准号:
    10794926
  • 负责人:
  • 金额:
    $ 3.98万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-01 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY / ABSTRACT Cardiovascular disease (CVD) is a leading cause of deaths in the United States, however the underlying inflammatory pathways that contribute to CVD are poorly understood. Endothelial dysfunction is a hallmark of CVD and induced by various inflammatory mediators, many of which signal through G-protein coupled receptor (GPCRs). Thrombin, an inflammatory mediator, is generated in response to vascular injury and disrupts endothelial barrier integrity and promotes vascular leakage, a hallmark of inflammation. Thrombin activates endothelial protease-activated receptor-1 (PAR1) to disrupt endothelial barrier through the RhoA/myosin light chain (MLC) pathway. However, thrombin/PAR1-stimulated p38 mitogen-activated protein kinase (MAPK) signaling also promotes barrier permeability through a pathway that does not integrate with the RhoA/MLC signaling, suggesting that p38 acts through an uncharacterized pathway to promote inflammatory responses in endothelial cells. Our previous work showed that thrombin-activated PAR1 ubiquitination drives the recruitment of TAB2-TAB1 protein complexes on endosomes to trigger non-canonical p38 activation and endothelial barrier disruption. The mechanisms that regulate PAR1 ubiquitination/de-ubiquitination are not known. This proposal aims to understand the molecular processes that regulate PAR1-ubiquitin-driven p38 signaling and most importantly its impact on endothelial barrier integrity. The central hypothesis is that de-ubiquitination of PAR1 leads to termination of p38-mediated pro-inflammatory signaling and will be tested with two specific aims: 1) To delineate the function of PAR1-specific deubiquitinases (DUBs) enzymes in the regulation of ubiquitin-driven p38 MAPK inflammatory signaling and 2) To study the functional impact of ubiquitination / de-ubiquitination of PAR1 on endothelial barrier permeability. Using advanced biochemical, microscopic and genome-wide RNAi screening methods, the proposed research plan will allow for the first time to investigate molecular determinants that regulate the dynamics of PAR1-ubiquitination and the impact on endothelial proinflammatory responses in vitro using human endothelial cells and in vivo using mice. The contribution of this work is expected to be significant as this study will reveal new information regarding the function of PAR1 ubiquitination in driving non-canonical endosomal p38 MAPK signaling in endothelial barrier disruption, a hallmark of inflammation and will further reveal a new signaling pathway that controls endothelial barrier function, which will provide an opportunity for the development new strategies for the treatment of inflammatory responses associated with CVD.
项目摘要/摘要

项目成果

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