Surfactant Protein C Mouse Models: A Fit For Purpose Preclinical Platform For Advancing Discovery In And Treatment Of Idiopathic Pulmonary Fibrosis

表面活性剂蛋白 C 小鼠模型:一个适合目的的临床前平台,可促进特发性肺纤维化的发现和治疗

基本信息

  • 批准号:
    10321882
  • 负责人:
  • 金额:
    $ 80.14万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-01-01 至 2024-12-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT Idiopathic Pulmonary fibrosis (IPF) is a devastating interstitial lung disease (ILD) of older adults characterized by disruption of distal lung architecture that ultimately leads to scar formation, abnormal gas exchange, and respiratory failure. A key barrier to developing better therapeutic outcomes for IPF has been a dearth of translationally relevant preclinical models. Based on a recent paradigm shift wherein the concepts of repetitive injury to a dysfunctional, vulnerable, alveolar epithelium coupled with an abnormal wound healing response are postulated as disease “drivers”, new opportunities are emerging for therapeutic discovery in IPF. Mutations in the alveolar type 2 cell (AT2) restricted, Surfactant Protein C [SP-C] gene [SFTPC], have been found in sporadic and familial IPF and provide important clues for understanding IPF pathogenesis. To address the unmet need for IPF patients, this proposal builds upon on a strong foundation of our prior work characterizing the cell biology of SP-C biosynthesis that culminated in generation of two novel knock-in mouse models of spontaneous lung fibrosis already in hand which express clinical SP-C mutants in AT2 cells in an allelic and inducible fashion. Our Published Data has demonstrated that clinical IPF associated SFTPC mutations produce aberrant SP-C proprotein isoforms that functionally segregate into 2 AT2 phenotypes: ER stress induced by intracellular SP-C misfolding (BRICHOS) or autophagy/mitophagy impaired from proSP-C mistrafficking to non-native organelles (Non-BRICHOS). When expressed in the lung epithelium in vivo, both the non-BRICHOS mutant (SftpcI73T) and the BRICHOS mutant (SftpcC121G) are extremely toxic to the lung and each is sufficient to evoke a time-dependent, physiologically restrictive peripheral fibrotic lung phenotype that elaborates translationally relevant biomarkers reported in human IPF. This proposal will leverage these unique models for Discovery, Target ID/ Validation, and Proof of Concept studies aimed at mapping cell subpopulations and uncovering novel pathways driving lung fibrosis whilst providing a compelling translational platform to interface with other preclinical/translational platforms in this U01 consortium to accelerate IPF therapeutic development. In 3 specific aims, we propose to utilize Sftpc mutant mice to map cell populations, transcriptomic profiles, and cell-cell crosstalk repertoires arising during evolution of spontaneous fibrotic lung phenotypes [Specific Aim 1], identify novel disease relevant biomarker candidates elaborated during the aberrant injury-repair process [Specific Aim 2], and assess the important contributions of and mechanisms by which aging and sex impact IPF phenotypes [Specific Aim 3]. Importantly, many of the endpoints defined in Sftpc models will be cross-validated and contextualized using lung tissue and serum from a well-phenotyped human IPF biorepository. When completed, the impactful deliverables produced from this project will include a new platform to better understand IPF pathogenesis from its onset through disease progression and serve as a resource for the broader research community to identify and test novel therapies to treat this disease.
摘要

项目成果

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MICHAEL FRANCIS BEERS其他文献

MICHAEL FRANCIS BEERS的其他文献

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{{ truncateString('MICHAEL FRANCIS BEERS', 18)}}的其他基金

COVID-19: Understanding The Role of Corona Virus InducedDisruption Of Alveolar Type 2 Cell Function And SurfactantHomeostasis In The Pathogenesis Of COVID-19 AcuteRespiratory Distress Syndrome
COVID-19:了解冠状病毒引起的肺泡 2 型细胞功能和表面活性剂稳态破坏在 COVID-19 急性呼吸窘迫综合征发病机制中的作用
  • 批准号:
    10744174
  • 财政年份:
    2021
  • 资助金额:
    $ 80.14万
  • 项目类别:
Surfactant Protein C Mouse Models: A Fit For Purpose Preclinical Platform For Advancing Discovery In And Treatment Of Idiopathic Pulmonary Fibrosis
表面活性剂蛋白 C 小鼠模型:一个适合目的的临床前平台,可促进特发性肺纤维化的发现和治疗
  • 批准号:
    10542732
  • 财政年份:
    2021
  • 资助金额:
    $ 80.14万
  • 项目类别:
COVID-19: Understanding The Role of Corona Virus InducedDisruption Of Alveolar Type 2 Cell Function And SurfactantHomeostasis In The Pathogenesis Of COVID-19 AcuteRespiratory Distress Syndrome
COVID-19:了解冠状病毒引起的肺泡 2 型细胞功能和表面活性剂稳态破坏在 COVID-19 急性呼吸窘迫综合征发病机制中的作用
  • 批准号:
    10152248
  • 财政年份:
    2021
  • 资助金额:
    $ 80.14万
  • 项目类别:
Surfactant Protein C Mouse Models: A Fit For Purpose Preclinical Platform For Advancing Discovery In And Treatment Of Idiopathic Pulmonary Fibrosis
表面活性剂蛋白 C 小鼠模型:一个适合目的的临床前平台,可促进特发性肺纤维化的发现和治疗
  • 批准号:
    10025851
  • 财政年份:
    2021
  • 资助金额:
    $ 80.14万
  • 项目类别:
COVID-19: Understanding The Role of Corona Virus InducedDisruption Of Alveolar Type 2 Cell Function And SurfactantHomeostasis In The Pathogenesis Of COVID-19 AcuteRespiratory Distress Syndrome
COVID-19:了解冠状病毒引起的肺泡 2 型细胞功能和表面活性剂稳态破坏在 COVID-19 急性呼吸窘迫综合征发病机制中的作用
  • 批准号:
    10367948
  • 财政年份:
    2021
  • 资助金额:
    $ 80.14万
  • 项目类别:
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:
    10165806
  • 财政年份:
    2019
  • 资助金额:
    $ 80.14万
  • 项目类别:
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
  • 财政年份:
    2019
  • 资助金额:
    $ 80.14万
  • 项目类别:
Biosynthesis and Trafficking of Surfactant Protein C In Health and Disease
表面活性剂蛋白 C 在健康和疾病中的生物合成和运输
  • 批准号:
    8559147
  • 财政年份:
    2013
  • 资助金额:
    $ 80.14万
  • 项目类别:
Biosynthesis and Trafficking of Surfactant Protein C In Health and Disease
表面活性剂蛋白 C 在健康和疾病中的生物合成和运输
  • 批准号:
    8731968
  • 财政年份:
    2013
  • 资助金额:
    $ 80.14万
  • 项目类别:
Biosynthesis and Trafficking of Surfactant Protein C In Health and Disease
表面活性剂蛋白 C 在健康和疾病中的生物合成和运输
  • 批准号:
    9281865
  • 财政年份:
    2013
  • 资助金额:
    $ 80.14万
  • 项目类别:

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