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Understanding how alveolar epithelial cell stress drives aberrant repair in interstitial lung disease

了解肺泡上皮细胞应激如何驱动间质性肺疾病的异常修复

基本信息

批准号：
10636819
负责人：
Jeremy Binder Katzen
金额：
$ 16.79万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10636819
关键词：
Address Adult Air Sacs Alveolar Alveolitis Alveolus Apoptosis Apoptotic Automobile Driving Autophagocytosis Bioinformatics Cell Culture Techniques Cell Line Cell Proliferation Cell model Cells Cellular Stress Cellular biology Child Chronic Disease Coupled Coupling Data Defect Development Disease Disease model Epithelial Cells Epithelium Fibrosis Functional disorder Gene Mutation Generations Genes Genetic Human In Vitro Induced Mutation Inflammation Injury Interstitial Lung Diseases Knock-in Knock-in Mouse Link Lung Lung diseases Mesenchymal Mesenchyme Modeling Molecular Mus Mutate Mutation Organoids Pathogenesis Pathologic Pathway interactions Patients Phenotype Play Pre-Clinical Model Prognosis Proliferating Protein Isoforms Proteins Publishing Pulmonary Fibrosis Pulmonary Pathology Pulmonary Surfactant-Associated Protein C Research Respiratory Failure Role Signal Pathway Signal Transduction System Techniques Therapeutic Therapeutically Targetable Training alveolar epithelium biological adaptation to stress citrate carrier endoplasmic reticulum stress fibrotic interstitial lung disease fibrotic lung disease human disease in vivo in vivo Model inhibition of autophagy injury and repair interstitial lung injury lung repair mouse model multimodality mutant novel patient subsets pharmacologic pre-clinical progenitor programs repaired segregation stem cell function stem cells surfactant theories therapeutic evaluation trafficking transcriptome sequencing

项目摘要

PROJECT SUMMARY Interstitial lung diseases (ILDs) are a class of pulmonary diseases pathologically defined by interstitial fibrosis and inflammation. Owing to our limited understanding of the upstream initiators of pathogenesis, ILDs have poor prognoses and limited therapeutics. Mutations in the Alveolar Epithelial Type 2 Cell (AEC2) restricted Surfactant Protein C (SP-C) gene (SFTPC) in a subset of ILD patients supports a growing hypothesis that AEC2 dysfunction is a driver of disease. When we model these disease-related SFTPC mutations in vitro they segregate into two major classes based upon how the mutated SP-C isoform stresses cellular pathways that manage abnormal proteins: mutations that inhibit macroautophagy and mutations that cause endoplasmic reticulum (ER) stress. However, how these AEC2 stress phenotypes, which have also been identified in ILD patients without SFTPC mutations, relate to ILD development remains poorly understood. To understand this relationship, we have generated two unique Sftpc mutation knock-in mouse models, one expressing an SP-C isoform that induces AEC2 macroautophagy dysfunction (SP-CI73T) and the other inducing ER stress (SP-CC121G). Each of these mutations when expressed in the adult mouse lung results in spontaneous alveolitis and lung injury followed by aberrant repair with resultant fibrotic ILD. These models thus provide proof of concept that AEC2 stress is capable of driving spontaneous lung pathology and are robust preclinical platforms. These models also support a second emerging theory of ILD pathogenesis: that in ILD AEC2s, which must act as critical facultative progenitor cells after lung injury by both proliferating and differentiating to repair damaged epithelium, develop dysfunction in their progenitor cell capacity. We discovered that while similar lung pathology develops in each of our Sftpc models, there are divergent AEC2 proliferation phenotypes following lung injury: SP-CI73T AEC2s become hyperpoliferative and SP-CC121G AEC2s become apoptotic and hypoproliferative. Thus, our models support the hypothesis that abnormal AEC2 progenitor cell function plays a central role in ILD development, and also create a platform to develop a mechanistic understanding of how discrete AEC2 stress signatures result in distinct defects in progenitor cell capacity. This proposal has three interrelated aims that seek to understand the molecular and cellular mechanisms that relate AEC2 cell stress, dysfunctional progenitor cell capacity, and ILD. Aim 1 uses bioinformatics and in vivo linage-tracing to characterize the AEC2 stress signaling and progenitor function pathways involved in each model. Aim 2 provides a mechanistic link between cell stress signaling and progenitor cell dysfunction through ex vivo organoid culture and in vivo modeling. In Aim 3 we will generate the first ILD patient-derived iPSC culture model of an ER stress associated SFTPC mutation as a humanized platform to study the pathways identified in Aims 1 and 2. This proposal will also provided the trainee with the diverse and comprehensive training necessary to develop a multimodal independent research program on the role of the epithelium in ILD.

项目总结