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
• 负责人: MICHAEL FRANCIS BEERS
• 金额: $ 79.15万
• 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/10542732
• 关键词: Acceleration; Address; Adult; Age; Aging; Alleles; Alveolar; Anabolism; Apoptosis; 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; Epithelium; Evolution; Fibrosis; Foundations; Functional disorder; Gases; Gene Expression Profile; Gene Mutation; Generations; Genes; Goals; Hand; High Resolution Computed Tomography; Histology; Human; Impairment; Injury; Interstitial Lung Diseases; Investigation; Knock-in; Knock-in Mouse; Ligands; Lung; Lung Transplantation; Maps; Medical; Medicine; 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; Transplantation; Usual Interstitial Pneumonia; Validation; Work; aged; alveolar epithelium; biobank; biomarker identification; candidate marker; cohort; endoplasmic reticulum stress; fibrogenesis; fibrotic lung; genetic variant; high resolution imaging; idiopathic pulmonary fibrosis; in vivo; inhibition of autophagy; injury and repair; insight; lung repair; mortality; mouse model; mutant; new therapeutic target; nintedanib; non-Native; novel; novel therapeutics; patient subsets; pre-clinical; primary endpoint; programs; radiological imaging; receptor; response; secondary endpoint; segregation; 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.

抽象的 特发性肺纤维化（IPF）是老年人的一种破坏性间质性肺疾病（ILD） 通过破坏远端肺结构，最终导致疤痕形成、气体交换异常，以及 呼吸衰竭。开发更好的 IPF 治疗结果的一个关键障碍是缺乏 转化相关的临床前模型。基于最近的范式转变，其中重复的概念 对功能失调的、脆弱的肺泡上皮的损伤加上异常的伤口愈合反应是 被认为是疾病的“驱动因素”，IPF 治疗发现的新机会正在出现。突变在 肺泡 2 型细胞 (AT2) 限制性表面活性蛋白 C [SP-C] 基因 [SFTPC] 已被发现 散发性和家族性IPF，为了解IPF发病机制提供重要线索。为了解决 针对 IPF 患者未满足的需求，该提案建立在我们之前的工作的坚实基础上，该工作的特点是 SP-C生物合成的细胞生物学最终产生了两种新型敲入小鼠模型 自发性肺纤维化已经在手，其在 AT2 细胞中以等位基因表达临床 SP-C 突变体 诱导时尚。我们发布的数据表明，临床 IPF 相关的 SFTPC 突变 产生异常的 SP-C 蛋白原亚型，在功能上分离成 2 个 AT2 表型：内质网应激 由细胞内 SP-C 错误折叠 (BRICHOS) 或 proSP-C 损伤的自噬/线粒体自噬诱导 错误贩运到非本地细胞器（Non-BRICHOS）。当体内表达于肺上皮时，两者 非 BRICHOS 突变体 (SftpcI73T) 和 BRICHOS 突变体 (SftpcC121G) 对肺有极大的毒性， 每一个都足以引起时间依赖性、生理限制性外周纤维化肺表型 详细阐述了人类 IPF 中报告的翻译相关生物标志物。该提案将利用这些独特的 用于发现、目标 ID/验证和概念验证研究的模型，旨在绘制细胞图 亚群并揭示驱动肺纤维化的新途径，同时提供令人信服的转化 与 U01 联盟中其他临床前/转化平台对接的平台，以加速 IPF 治疗的发展。在 3 个具体目标中，我们建议利用 Sftpc 突变小鼠来绘制细胞群图谱， 自发性纤维化肺进化过程中出现的转录组谱和细胞间串扰库 表型[具体目标 1]，识别新的疾病相关候选生物标志物 异常的损伤修复过程[具体目标2]，并评估其重要贡献和机制 衰老和性别会影响 IPF 表型 [具体目标 3]。重要的是，许多端点定义在 Sftpc 模型将使用表型良好的肺组织和血清进行交叉验证和背景化 人类IPF生物样本库。完成后，该项目产生的有影响力的交付成果将包括 新平台可以更好地了解 IPF 从发病到疾病进展的发病机制，并作为 为更广泛的研究界提供资源，以确定和测试治疗这种疾病的新疗法。