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.
项目摘要
特发性肺纤维化(IPF)是一种慢性肺部疾病,诊断后的中位生存期为3年。
这种病无药可医。虽然病因尚不清楚,但与之相关的主要危险因素之一是
IPF的主要原因是吸入富含铁的颗粒物,如石棉和香烟烟雾。然而,具体作用
铁在IPF发病机制中的作用是一个研究不足的领域。本项目的长期目标是阐明
IPF的发病机制,从而促进有效疗法的开发。当前的目标
应用的目的是了解铁对IPF发病机制的作用及其潜在机制
重点关注铁介导的肺成纤维细胞激活。
有证据表明,铁在肺中积聚并导致肺纤维化。但
这两个过程的分子机制尚不清楚。我们的初步研究已经确定了
基因溶质载体家族40成员1(SLC40A1)作为肺成纤维细胞中铁积累的关键基因。我们
还鉴定了两个新的铁调节基因,SH3结构域含环指1(SH3RF1),E3
泛素蛋白连接酶和同源结构域相互作用蛋白激酶2(HIPK2),一种共转录调节因子,
提供了两种基因调节肺成纤维细胞活化的证据。根据我们的初步研究,
总的假设是,由于SLC 40 A1减少,肺成纤维细胞中铁水平升高,
通过下调SH3RF1表达和上调HIPK2激活肺成纤维细胞
表情该假设将通过使用原代人肺的体外研究组合进行检验。
在两种小鼠肺纤维化模型中,使用药理学和遗传学方法,
干预措施。目的探讨铁在肺成纤维细胞中通过SLC40A1表达的机制
以及SH3RF1在铁介导的肺成纤维细胞活化中的调节和功能作用,
功能获得和诱变方法。目的二将明确铁激活肺的机制
利用基因操作、免疫共沉淀、泛素化和分子信号转导通过HIPK2对成纤维细胞进行调控
路径分析目的III将确定铁和HIPK2在两个临床前实验中对肺纤维化的体内作用。
使用成纤维细胞特异性基因缺失的博莱霉素和石棉诱导的肺纤维化小鼠模型
Hipk2和药理学抑制剂。这些研究将建立铁的分子机制
在肺成纤维细胞中的积累以及SH3RF1和HIPK2在肺成纤维细胞活化中的新作用。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
LIN LIU其他文献
LIN LIU的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Impact of alternative polyadenylation of 3'-untranslated regions in the PI3K/AKT cascade on microRNA
PI3K/AKT 级联中 3-非翻译区的替代多聚腺苷酸化对 microRNA 的影响
- 批准号:
573541-2022 - 财政年份:2022
- 资助金额:
$ 46.95万 - 项目类别:
University Undergraduate Student Research Awards
How do untranslated regions of cannabinoid receptor type 1 mRNA determine receptor subcellular localisation and function?
1 型大麻素受体 mRNA 的非翻译区如何决定受体亚细胞定位和功能?
- 批准号:
2744317 - 财政年份:2022
- 资助金额:
$ 46.95万 - 项目类别:
Studentship
MICA:Synthetic untranslated regions for direct delivery of therapeutic mRNAs
MICA:用于直接递送治疗性 mRNA 的合成非翻译区
- 批准号:
MR/V010948/1 - 财政年份:2021
- 资助金额:
$ 46.95万 - 项目类别:
Research Grant
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10019570 - 财政年份:2019
- 资助金额:
$ 46.95万 - 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10223370 - 财政年份:2019
- 资助金额:
$ 46.95万 - 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10455108 - 财政年份:2019
- 资助金额:
$ 46.95万 - 项目类别:
Synergistic microRNA-binding sites, and 3' untranslated regions: a dialogue of silence
协同的 microRNA 结合位点和 3 非翻译区:沉默的对话
- 批准号:
255762 - 财政年份:2012
- 资助金额:
$ 46.95万 - 项目类别:
Operating Grants
Analysis of long untranslated regions in Nipah virus genome
尼帕病毒基因组长非翻译区分析
- 批准号:
20790351 - 财政年份:2008
- 资助金额:
$ 46.95万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Search for mRNA elements involved in the compatibility between 5' untranslated regions and coding regions in chloroplast translation
寻找参与叶绿体翻译中 5 非翻译区和编码区之间兼容性的 mRNA 元件
- 批准号:
19370021 - 财政年份:2007
- 资助金额:
$ 46.95万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Post-transcriptional Regulation of PPAR-g Expression by 5'-Untranslated Regions
5-非翻译区对 PPAR-g 表达的转录后调控
- 批准号:
7131841 - 财政年份:2006
- 资助金额:
$ 46.95万 - 项目类别: