A Novel PAI-1 Function Drives Lung Fibrosis

PAI-1 的新功能可驱动肺纤维化

基本信息

  • 批准号:
    10605479
  • 负责人:
  • 金额:
    $ 69.67万
  • 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:
    2022-12-15 至 2026-11-30
  • 项目状态:
    未结题

项目摘要

Project Summary Progressive scarring of the lung interstitium is a common feature of many systemic and primary lung diseases including Idiopathic Pulmonary Fibrosis (IPF). IPF is a common disorder, and patients diagnosed with this disorder experience substantial morbidity and a median survival of 3-5 years. Although recently approved therapies slow the rate of disease progression, more efficacious interventions that interfere with precise disease mechanisms are desperately needed. Plasminogen activator inhibitor-1 (PAI-1) holds substantial promise as a therapeutic target for lung fibrosis as experiments in multiple complementary animal models reveal a direct correlation between the activity of this molecule and the severity of scarring. These studies substantiate PAI-1 as a critical down-stream mediator of prominent pro-fibrotic stimuli including TGF-β and matrix stiffness. Despite the large amount of data implicating PAI-1 as a critical pro-fibrotic protein, the mechanism by which it promotes fibrosis remains elusive. PAI-1 is a multifunctional protein with inhibitory activity against the plasminogen activators through which it regulates fibrinolysis and wound healing. PAI-1 also interacts with non-protease ligands including the provisional matrix protein vitronectin (VTN). Using mutant proteins lacking specific functions and transgenic mice, we demonstrated that the pro-fibrotic action of PAI-1 is largely independent of its plasminogen activator inhibitory activity and that vitronectin is not required for PAI-1 to fully promote scarring of the lung. These results led us to perform an unbiased proteomic study to identify novel PAI-1 binding partners within the injured lung. With this approach, we identified sortilin related receptor-1 (SorlA) as the most enriched protein. SorlA is a multi-domain receptor implicated in the uptake and intracellular sorting of proteins. Our preliminary data confirm that PAI-1 binds to SorlA and that this interaction is prevented by mutations that suppress the profibrotic activity of PAI-1. We further find that PAI-1 is taken up by key cellular constituents of the fibrotic lesion. Importantly, we also identify a previously unrecognized and potent role for SorlA in lung fibrosis, and using human cells, we find that SorlA expression is upregulated in fibrotic epithelial cells and fibroblasts. These preliminary data motivate our hypothesis that PAI-1 promotes lung fibrosis through an interaction with SorlA that leads to cell uptake, cytosolic localization, and a profibrotic alteration in cell phenotype. To interrogate this hypothesis, we have designed a multifaceted approach incorporating molecular biology techniques, in vitro experiments with cells from patients and mice (as well as cell lines), and in vivo experiments using transgenic mice, mutant PAI-1 proteins, and complementary models of lung fibrosis. To accomplish our proposed studies, we have brought together a synergistic investigative team with expertise in PAI-1, epithelial cell and fibroblast biology, and animal modeling, and the results from our studies promise to elucidate previously unexplored mechanisms and novel therapeutic targets.
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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Daniel A Lawrence其他文献

Plasminogen promotes sarcoma growth and suppresses the accumulation of tumor-infiltrating macrophages
纤溶酶原促进肉瘤生长并抑制肿瘤浸润巨噬细胞的积累
  • DOI:
    10.1038/sj.onc.1205951
  • 发表时间:
    2002-12-16
  • 期刊:
  • 影响因子:
    7.300
  • 作者:
    Alejandro Curino;David J Mitola;Hannah Aaronson;Grainne A McMahon;Kamran Raja;Achsah D Keegan;Daniel A Lawrence;Thomas H Bugge
  • 通讯作者:
    Thomas H Bugge

Daniel A Lawrence的其他文献

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{{ truncateString('Daniel A Lawrence', 18)}}的其他基金

Characterization and targeting of a novel pathway promoting Parkinson’s Disease
促进帕金森病的新途径的表征和靶向
  • 批准号:
    10855706
  • 财政年份:
    2023
  • 资助金额:
    $ 69.67万
  • 项目类别:
The Role of PAI-1 in Cerebral Microvascular Dysfunction and the Development of Alzheimer’s Disease Neuropathology
PAI-1 在脑微血管功能障碍和阿尔茨海默病发展中的作用 神经病理学
  • 批准号:
    10314556
  • 财政年份:
    2021
  • 资助金额:
    $ 69.67万
  • 项目类别:
The Role of PAI-1 in Cerebral Microvascular Dysfunction and the Development of Alzheimer’s Disease Neuropathology
PAI-1 在脑微血管功能障碍和阿尔茨海默病发展中的作用 神经病理学
  • 批准号:
    10629303
  • 财政年份:
    2021
  • 资助金额:
    $ 69.67万
  • 项目类别:
Mechanism of thrombolytic tPA induced intracerebral hemorrhage after stroke
溶栓tPA致脑卒中后脑出血的机制
  • 批准号:
    8655918
  • 财政年份:
    2012
  • 资助金额:
    $ 69.67万
  • 项目类别:
Mechanism of thrombolytic tPA induced intracerebral hemorrhage after stroke
溶栓tPA致脑卒中后脑出血的机制
  • 批准号:
    8487469
  • 财政年份:
    2012
  • 资助金额:
    $ 69.67万
  • 项目类别:
Mechanism of thrombolytic tPA induced intracerebral hemorrhage after stroke
溶栓tPA致脑卒中后脑出血的机制
  • 批准号:
    8345099
  • 财政年份:
    2012
  • 资助金额:
    $ 69.67万
  • 项目类别:
Characterization of the role of PAI-1 in lipid metabolism
PAI-1 在脂质代谢中的作用表征
  • 批准号:
    8247042
  • 财政年份:
    2011
  • 资助金额:
    $ 69.67万
  • 项目类别:
Laboratory Testing Core
实验室测试核心
  • 批准号:
    8247047
  • 财政年份:
    2011
  • 资助金额:
    $ 69.67万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    8247048
  • 财政年份:
    2011
  • 资助金额:
    $ 69.67万
  • 项目类别:
Laboratory Testing Core
实验室测试核心
  • 批准号:
    8150067
  • 财政年份:
    2010
  • 资助金额:
    $ 69.67万
  • 项目类别:

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