权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
LIN LIU
金额：
$ 46.95万
依托单位：
OKLAHOMA STATE UNIVERSITY STILLWATER
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：
https://reporter.nih.gov/project-details/10586471
关键词：
3&apos Untranslated Regions Actins Advanced Development Anemia Area Asbestos Binding Bleomycin Chronic lung disease Co-Immunoprecipitations Development Diagnosis Disease Down-Regulation Elements Etiology FDA approved Family Fibroblasts Genes Genetic Genetic Transcription Goals Homeostasis Human In Vitro Individual Inhalation Invaded Ions Iron Iron Chelation Iron-Regulatory Proteins Lung Mediating Messenger RNA Modeling Molecular Mus Mutagenesis Names Particulate Matter Pathogenesis Pathway Analysis Pathway interactions Persons Pharmaceutical Preparations Process Protein Kinase Interaction Proteins Pulmonary Fibrosis Regulation Ring Finger Domain Risk Factors Role SH3 Domains Signal Pathway Smooth Muscle Stress Fibers Testing Translations Treatment Efficacy Ubiquitination United States Up-Regulation cigarette smoke effective therapy fibrotic lung gain of function gene therapy genetic manipulation genome-wide homeodomain idiopathic pulmonary fibrosis in vivo inhibitor insight iron supplementation kidney fibrosis knock-down loss of function mRNA Stability member mouse development mouse model novel overexpression pharmacologic pre-clinical solute ubiquitin-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