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
- 来源:
- 关键词:AfibrinogenemiaAgingAlzheimer&aposs DiseaseAnimal ModelAtherosclerosisAttenuatedAutomobile DrivingBindingBiologyBiotinBleomycinCell LineCell Surface ReceptorsCellsCessation of lifeChimeric ProteinsCicatrixConfocal MicroscopyCytoplasmDataDiagnosisDiseaseDisease PathwayDisease ProgressionEndocytosisEpithelial CellsEssential Amino AcidsFibrinolysisFibroblastsFibrosisFoundationsGene DeletionHeartHumanIn VitroIncidenceKidneyKnock-in MouseLabelLesionLigandsLigaseLiverLungLung diseasesMediatingMediatorModelingMolecular Biology TechniquesMorbidity - disease rateMusMutationOrganPathway interactionsPatientsPhage DisplayPharmaceutical PreparationsPhenotypePlasminogen ActivatorPlasminogen Activator Inhibitor 1Plasminogen Activator InteractionProfibrotic signalProtein SortingsProteinsProteomicsPulmonary FibrosisRegulationRoleSeveritiesShortness of BreathSkinStimulusSurface Plasmon ResonanceTestingTherapeuticTissuesTransforming Growth Factor betaTransgenic MiceUrokinaseVitronectinalveolar epitheliumdesignefficacious interventionefficacious treatmentexperienceexperimental studyfibrogenesisfibrotic lungidiopathic pulmonary fibrosisin vivoinhibitorlung developmentlung injurymortalitymosaicmouse modelmutantmutation screeningnew therapeutic targetnoveloverexpressionpreventprotein reconstitutionprototypereceptorsmall moleculesortilintherapeutic targetuptakevalidation studieswound healing
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)
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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
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The Role of PAI-1 in Cerebral Microvascular Dysfunction and the Development of Alzheimer’s Disease Neuropathology
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- 批准号:
10314556 - 财政年份:2021
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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
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Mechanism of thrombolytic tPA induced intracerebral hemorrhage after stroke
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8655918 - 财政年份:2012
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Mechanism of thrombolytic tPA induced intracerebral hemorrhage after stroke
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