The Role of Iron In Pulmonary Fibrosis
铁在肺纤维化中的作用
基本信息
- 批准号:10586471
- 负责人:
- 金额:$ 46.95万
- 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:2022-12-01 至 2026-11-30
- 项目状态:未结题
- 来源:
- 关键词:3&apos Untranslated RegionsActinsAdvanced DevelopmentAnemiaAreaAsbestosBindingBleomycinChronic lung diseaseCo-ImmunoprecipitationsDevelopmentDiagnosisDiseaseDown-RegulationElementsEtiologyFDA approvedFamilyFibroblastsGenesGeneticGenetic TranscriptionGoalsHomeostasisHumanIn VitroIndividualInhalationInvadedIonsIronIron ChelationIron-Regulatory ProteinsLungMediatingMessenger RNAModelingMolecularMusMutagenesisNamesParticulate MatterPathogenesisPathway AnalysisPathway interactionsPersonsPharmaceutical PreparationsProcessProtein Kinase InteractionProteinsPulmonary FibrosisRegulationRing Finger DomainRisk FactorsRoleSH3 DomainsSignal PathwaySmooth MuscleStress FibersTestingTranslationsTreatment EfficacyUbiquitinationUnited StatesUp-Regulationcigarette smokeeffective therapyfibrotic lunggain of functiongene therapygenetic manipulationgenome-widehomeodomainidiopathic pulmonary fibrosisin vivoinhibitorinsightiron supplementationkidney fibrosisknock-downloss of functionmRNA Stabilitymembermouse developmentmouse modelnoveloverexpressionpharmacologicpre-clinicalsoluteubiquitin-protein ligase
项目摘要
PROJECT SUMMARY
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with a median survival of 3 years after diagnosis.
There are no cures for this disease. Although the etiology is still unclear, one of the major risk factors associated
with IPF is inhaled iron-rich particulate matter, such as asbestos and cigarette smoke. However, the specific role
of iron in the pathogenesis of IPF is an understudied area. The long-term goal of this project is to elucidate the
pathogenesis of IPF and thus to advance the development of effective therapies. The objective of the current
application is to understand the contribution of iron to the pathogenesis of IPF and the underlying mechanisms
with a focus on the iron-mediated activation of lung fibroblasts.
There is evidence showing that iron accumulates in the lung and contributes to lung fibrosis. However, the
molecular mechanisms for both processes are unclear. Our preliminary studies have identified the iron export
gene solute carrier family 40 member 1 (SLC40A1) as a key gene for iron accumulation in lung fibroblasts. We
have also identified two novel iron-regulated genes, SH3 domain-containing ring finger 1 (SH3RF1), an E3
ubiquitin protein ligase, and homeodomain-interacting protein kinase 2 (HIPK2), a cotranscriptional regulator and
provided evidence that both genes regulate lung fibroblast activation. Based on our preliminary studies, our
overall hypothesis is that an elevated level of iron in lung fibroblasts due to reduced SLC40A1 leads to the
activation of lung fibroblasts via the downregulation of SH3RF1 expression and the upregulation of HIPK2
expression. The hypothesis will be tested by a combination of in vitro studies using primary human lung
fibroblasts and in vivo strategies in two mouse lung fibrosis models using pharmacological and genetic
interventions. Aim I will determine the mechanisms by which iron accumulates in lung fibroblasts via SLC40A1
and the regulation and functional roles of SH3RF1 in iron-mediated lung fibroblast activation using loss- and
gain-of-function and mutagenesis approaches. Aim II will define the mechanisms by which iron activates lung
fibroblasts via HIPK2 using gene manipulation, coimmunoprecipitation, ubiquitination and molecular signaling
pathway analyses. Aim III will determine the in vivo effects of iron and HIPK2 on lung fibrosis in two preclinical
mouse models of bleomycin- and asbestos-induced lung fibrosis using fibroblast-specific genetic deletion of
Hipk2 and pharmacological inhibitors. The proposed studies will establish the molecular mechanisms of iron
accumulation in lung fibroblasts and novel roles for SH3RF1 and HIPK2 in lung fibroblast activation.
项目总结
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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{{ truncateString('LIN LIU', 18)}}的其他基金
Oklahoma Center for Respiratory and Infectious Diseases
俄克拉荷马州呼吸和传染病中心
- 批准号:
10628212 - 财政年份:2023
- 资助金额:
$ 46.95万 - 项目类别:
Lnc-PINK regulation of innate immunity in lung epithelial cells
Lnc-PINK对肺上皮细胞先天免疫的调节
- 批准号:
10365976 - 财政年份:2021
- 资助金额:
$ 46.95万 - 项目类别:
Oklahoma Center for Respiratory and Infectious Diseases
俄克拉荷马州呼吸和传染病中心
- 批准号:
10215542 - 财政年份:2013
- 资助金额:
$ 46.95万 - 项目类别:
Oklahoma Center for Respiratory and Infectious Diseases
俄克拉荷马州呼吸和传染病中心
- 批准号:
8686887 - 财政年份:2013
- 资助金额:
$ 46.95万 - 项目类别:
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