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Alveolar Epithelial Cell Dysfunction in Pulmonary Fibrosis: Leveraging SFTPC Mutations for Discovery of Molecular and Cellular Targets

Alveolar Epithelial Cell Dysfunction in Pulmonary Fibrosis: Leveraging SFTPC Mutations for Discovery of Molecular and Cellular Targets
肺纤维化中的肺泡上皮细胞功能障碍:利用 SFTPC 突变发现分子和细胞靶点
批准号:
10407546
负责人:
MICHAEL FRANCIS BEERS
金额:
$55.15万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-06-01 至 2024-05-31

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英文摘要
ABSTRACT Fibrotic lung remodeling represents the final common pathway to respiratory failure for a variety of Interstitial Lung Diseases (ILD) in children and adults. Based on a recent paradigm shift wherein the concepts of epithelial cell dysfunction and abnormal wound healing are postulated as “drivers” of pulmonary fibrosis, new opportunities are emerging for therapeutic discovery for ILD. Mutations in the Surfactant Protein C [SP-C] gene [SFTPC], an alveolar type 2 cell (AT2) restricted protein, have been found in sporadic and familial ILD and can provide important clues for understanding the role of epithelial cell dysfunction in ILD pathogenesis. Prior in vitro studies from our lab have shown that SFTPC mutations described in both adults and children with ILD result in production of aberrant SP-C proprotein isoforms that adopt non-native conformations resulting in at least 2 outcomes: ER stress and intracellular aggregation (BRICHOS) or mistrafficking to non-native organelles and inhibition of macroautophagy (Non-BRICHOS). This application proposes to leverage two novel knock-in mouse models of spontaneous lung fibrosis already in hand which express Non-BRICHOS or BRICHOS clinical SFTPC mutants in AT2 cells in an allelic and inducible fashion. Our Published and Preliminary Data reveal that expression of either a non-BRICHOS mutant (SP-CI73T) or BRICHOS mutant (SP- CC121G) is extremely toxic to the lung in vivo with each resulting in time-dependent spontaneous lung fibrosis marked by 3 phases: ii) early AT2 cytokine elaboration and monocyte recruitment,; (ii) a polycellular alveolitis and lung injury; (iii) physiologically restrictive peripheral fibrotic remodeling. These models also elaborate translationally relevant biomarkers reported in human ILD. In order to define both consensus and divergent molecular mechanisms linking these two AT2 cell phenotypes with the downstream lung injury and fibrotic lung remodeling, our experimental approach will be to exploit the unique features of these genetic models combined with tools, reagents, and expertise available in our program. In 3 specific aims, we propose to comprehensively characterize the transcriptomic and functional AT2 cell phenotypes evoked by expression of non-BRICHOS (SP-CI73T) and BRICHOS (SP-CC121G) Sftpc mutants [Specific Aim 1], to define the role of a key proinflammatory/profibrotic monocyte population recruited by AT2 mutant Sftpc expression in the development of fibrosis [Specific Aim 2], and to examine changes in epithelial-mesenchymal crosstalk that disrupt alveolar niche homeostasis and promote fibrotic remodeling [Specific Aim 3]. As epithelial dysfunction has not been studied extensively in vivo in the context of relevant preclinical models of fibrotic lung disease, this approach offers the unique opportunity to provide proof of concept both for the causal effect of mutant SFTPC in familial ILD and for the role of AT2 dysfunction as a key upstream driver of inflammatory cell and fibroblast activities that promote parenchymal remodeling. Importantly, mechanisms identified using a focused approach with these Sftpc models can be cross-purposed to better understand the pathogenesis of sporadic forms of ILD.
期刊论文(9)
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会议论文
DOI: 10.1002/adma.202202992
发表时间: 2022-07
期刊: ADVANCED MATERIALS
影响因子: 29.4
作者: [Loebel, Claudia, Weiner, Aaron, I, Eiken, Madeline K., Katzen, Jeremy B., Morley, Michael P., Bala, Vikram, Cardenas-Diaz, Fabian L., Davidson, Matthew D., Shiraishi, Kazushige, Basil, Maria C., Ferguson, Laura T., Spence, Jason R., Ochs, Matthias, Beers, Michael F., Morrisey, Edward E., Vaughan, Andrew E., Burdick, Jason A.]
通讯作者: Burdick, Jason A.
DOI: 10.1186/s12931-021-01860-3
发表时间: 2021-10-24
期刊: Respiratory research
影响因子: 5.8
作者: [Sivakumar P, Ammar R, Thompson JR, Luo Y, Streltsov D, Porteous M, McCoubrey C, Cantu E 3rd, Beers MF, Jarai G, Christie JD]
通讯作者: Christie JD
Chronic Expression of a Clinical SFTPC Mutation Causes Murine Lung Fibrosis with Idiopathic Pulmonary Fibrosis Features.
临床 SFTPC 突变的慢性表达导致具有特发性肺纤维化特征的小鼠肺纤维化。
DOI: 10.1165/rcmb.2022-0203ma
发表时间: 2023
期刊: American journal of respiratory cell and molecular biology
影响因子: 6.4
作者: [Rodriguez,Luis, Tomer,Yaniv, Carson,Paige, Dimopoulos,Thalia, Zhao,Ming, Chavez,Katrina, Iyer,Swati, Huang,Li, Ebert,Christina, Sereda,Larisa, Murthy,Aditi, Trujillo,Glenda, Beers,MichaelF, Katzen,Jeremy]
通讯作者: Katzen,Jeremy
DOI: 10.3389/fphar.2022.875887
发表时间: 2022
期刊: FRONTIERS IN PHARMACOLOGY
影响因子: 5.6
作者: [Nguyen, Jacklyn, Armstrong, Brittnie S., Cowman, Sophie, Tomer, Yaniv, Veerabhadraiah, Shivakumar R., Beers, Michael F., Venosa, Alessandro]
通讯作者: Venosa, Alessandro
6
    Surfactant Protein C Mouse Models: A Fit For Purpose Preclinical Platform For Advancing Discovery In And Treatment Of Idiopathic Pulmonary Fibrosis
    • 批准号:
      10321882
    • 项目类别:
    • 资助金额:
      $80.14万
    • 财政年份:
      2021
    • 负责人:
      MICHAEL FRANCIS BEERS
    • 依托单位:
    Surfactant Protein C Mouse Models: A Fit For Purpose Preclinical Platform For Advancing Discovery In And Treatment Of Idiopathic Pulmonary Fibrosis
    • 批准号:
      10542732
    • 项目类别:
    • 资助金额:
      $79.15万
    • 财政年份:
      2021
    • 负责人:
      MICHAEL FRANCIS BEERS
    • 依托单位:
    海外基金