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: 10321882
• 负责人: MICHAEL FRANCIS BEERS
• 金额: $ 80.14万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10321882
• 关键词: Address; Adult; Age; Aging; Alleles; Alveolar; Anabolism; Architecture; Automobile Driving; Autophagocytosis; Biological Markers; Bronchoalveolar Lavage Fluid; Cells; Cellular Stress; Cellular biology; Cessation of life; Characteristics; Chronic; Cicatrix; Clinical; Communities; Complication; Coupled; Data; Dependence; Development; Disease; Disease Progression; Distal; Elderly; Elements; Epithelial; Evolution; Fibrosis; Foundations; Functional disorder; Gases; Gene Expression Profile; Generations; Genes; Goals; Gold; Hand; High Resolution Computed Tomography; Histology; Human; Impairment; Injury; Interstitial Lung Diseases; Investigation; Knock-in; Knock-in Mouse; Ligands; Lung; Lung Transplantation; Maps; Medical; Mesenchymal; Modeling; Morbidity - disease rate; Mus; Mutant Strains Mice; Mutation; Organelles; Organoids; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Peripheral; Phenotype; Physiological; Physiology; Pirfenidone; Population; Pre-Clinical Model; Process; Protein Isoforms; Proteomics; Published Comment; Publishing; Pulmonary Fibrosis; Pulmonary Surfactant-Associated Protein C; Quality Control; Refractory; Reporting; Research; Resources; Respiratory Failure; Sampling; Serum; Signal Pathway; Stress; Structure of parenchyma of lung; Syndrome; Testing; Therapeutic; Time; Usual Interstitial Pneumonia; Validation; Work; aged; alveolar epithelium; base; biobank; candidate marker; cohort; endoplasmic reticulum stress; fibrogenesis; fibrotic lung; genetic variant; high resolution imaging; idiopathic pulmonary fibrosis; in vivo; induced pluripotent stem cell; injury and repair; insight; lung repair; mortality; mouse model; mutant; new therapeutic target; nintedanib; non-Native; novel; novel therapeutics; pre-clinical; primary endpoint; programs; radiological imaging; receptor; response; secondary endpoint; sex; single-cell RNA sequencing; therapeutic development; therapy outcome; trafficking; transcriptomics; validation studies; wound healing

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