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
• 负责人: MICHAEL FRANCIS BEERS
• 金额: $ 61.63万
• 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/10025851
• 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; Diagnostic radiologic examination; Disease; Disease Progression; Distal; Elderly; Elements; Epithelial; Evolution; Fibrosis; Foundations; Functional disorder; Gases; Gene Expression Profile; Generations; Genes; Goals; Gold; Hamman-Rich syndrome; 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; Validation; Work; aged; alveolar epithelium; base; biobank; candidate marker; cohort; endoplasmic reticulum stress; fibrogenesis; genetic variant; high resolution imaging; idiopathic pulmonary fibrosis; in vivo; induced pluripotent stem cell; injury and repair; insight; mortality; mouse model; mutant; new therapeutic target; non-Native; novel; novel therapeutics; pre-clinical; primary endpoint; programs; receptor; response; secondary endpoint; sex; single-cell RNA sequencing; therapeutic development; therapy outcome; tissue repair; 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）是一种毁灭性的间质性肺疾病（ILD） 通过破坏盘状肺建筑，最终导致疤痕形成，异常气体交换和 呼吸衰竭。为IPF开发更好治疗结果的关键障碍是死亡 翻译相关的临床前模型。基于最近的范式转移，重复性的概念 损伤功能失调，脆弱的肺泡上皮以及异常伤口愈合反应的损伤是 被认为是疾病“驱动因素”，在IPF中发现了新的机会。突变 在 零星和家庭IPF，为理解IPF发病机理提供了重要的线索。解决 对IPF患者的需求未满足，该提案基于我们先前的工作的强大基础 SP-C生物合成的细胞生物学，最终产生了两种新型的敲入小鼠模型 已经掌握了赞助的肺纤维化，在等位基因和 诱导时尚。我们已发布的数据表明，临床IPF相关的SFTPC突变 产生异常的SP-C普罗蛋白同工型，在功能上分离为2 AT2表型：ER应力 由细胞内SP-C错误折叠（Brichos）或prosp-C受损的自噬/线索造成的诱导 对非本地细胞器（非砖）造成了损害。当体内肺上皮表达时，两者都 非砖突变体（SFTPCI73T）和Brichos突变体（SFTPCC121G）对肺和 每个都足以唤起时间依赖，身体限制性的外周纤维化肺表型 详细说明了人类IPF中报告的翻译相关生物标志物。该建议将利用这些独特的 旨在绘制细胞的发现，目标ID/验证和概念研究证明的模型 亚群和发现驱动肺纤维化的新型途径，同时提供引人注目的翻译 与该U01联盟中其他临床前/翻译平台交互的平台以加速IPF 治疗发展。在3个特定目标中，我们建议利用SFTPC突变小鼠来绘制细胞群体， 转录组轮廓和细胞串扰曲线库在自发纤维化肺的进化过程中产生 表型[特定目标1]，确定新型疾病相关的生物标志物候选者 异常伤害修复过程[特定目标2]，并通过 衰老和性别影响IPF表型[特定目标3]。重要的是，在 SFTPC模型将通过肺组织和血清进行跨验证和情境化。 人类IPF生物座席。完成后，该项目产生的有影响力的可交付成果将包括 从疾病发展到IPF发病机理，可以更好地了解IPF发病机理的新平台 更广泛的研究界的资源来识别和测试新型疗法以治疗这种疾病。