The Role of Iron In Pulmonary Fibrosis

铁在肺纤维化中的作用

• 批准号: 10838699
• 负责人: LIN LIU
• 金额: $ 1.71万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-23 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10838699
• 关键词: Advanced Development; Area; Asbestos; Bleomycin; Chronic lung disease; Co-Immunoprecipitations; Development; Diagnosis; Disease; Down-Regulation; Etiology; Family; Fibroblasts; Genes; Genetic; Genetic Transcription; Goals; Human; In Vitro; Individual; Inhalation; Iron; Lung; Mediating; Modeling; Molecular; Mus; Mutagenesis; Particulate Matter; Pathogenesis; Pathway Analysis; Pathway interactions; Persons; Process; Protein Kinase Interaction; Pulmonary Fibrosis; Regulation; Ring Finger Domain; Risk Factors; Role; SH3 Domains; Signal Pathway; Testing; Ubiquitination; United States; Up-Regulation; cigarette smoke; effective therapy; gain of function; gene therapy; genetic manipulation; homeodomain; idiopathic pulmonary fibrosis; in vivo; inhibitor; insight; loss of function; member; mouse model; novel; pharmacologic; pre-clinical; solute; ubiquitin-protein ligase

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