Molecular Determinants of Usual Interstitial Pneumonia (UIP)

普通间质性肺炎 (UIP) 的分子决定因素

• 批准号: 10440715
• 负责人: David Albert Schwartz
• 金额: $ 72.59万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440715
• 关键词: Address; Affect; Antigens; Asbestosis; Binding; Biological; Biological Assay; Biology; Cell Nucleus; Cells; Characteristics; Chromatin; Chronic; Clinical; Complication; Data; Development; Disease; Distal; Dominant Genetic Conditions; Drug Targeting; Elements; Enhancers; Epigenetic Process; Epithelial; Etiology; Exposure to; Extrinsic allergic alveolitis; Fibroblasts; Fibrosis; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genotype; Goals; Heterogeneity; Immunohistochemistry; In Situ Hybridization; In Vitro; Individual; Interstitial Lung Diseases; Interstitial Pneumonia; Investigation; Lead; Lung; Lung diseases; MUC5B gene; Methods; Molecular; Molecular Profiling; Morphology; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Publishing; Pulmonary Fibrosis; Quantitative Trait Loci; Regulator Genes; Regulatory Pathway; Reporting; Research; Rheumatoid Arthritis; Risk Factors; Small Nuclear RNA; Structure of parenchyma of lung; Testing; Transcription Factor 3; Transcriptional Regulation; Transposase; Usual Interstitial Pneumonia; Variant; airway epithelium; cell type; combinatorial; disease phenotype; endoplasmic reticulum stress; epigenetic regulation; gain of function; gene regulatory network; genetic risk factor; genetic variant; idiopathic pulmonary fibrosis; indexing; multiple omics; novel; promoter; radiological imaging; risk variant; transcription regulatory network; transcriptome sequencing

ABSTRACT: The overall goal of this proposal is to understand how the gain-of-function MUC5B promoter variant affects transcriptional regulation and gene expression that are common to clinically distinct types of usual interstitial pneumonia (UIP). UIP was initially described as a morphologic entity, however, recently has been defined using specific pathologic and radiographic criteria. While UIP is characteristic of idiopathic pulmonary fibrosis (IPF), these pathologic and radiographic patterns of chronic fibrosing interstitial pneumonia are also typical of chronic hypersensitivity pneumonitis (CHP), rheumatoid arthritis-associated interstitial lung disease (RA-ILD), asbestosis, and several drug-induced lung diseases. The gain-of-function promoter variant in MUC5B (rs35705950) is the dominant risk factor for IPF, is present in >50% of affected patients, and has also been reported to be the dominant genetic risk variant for the development of CHP and RA-ILD. However, while IPF is by definition idiopathic, CHP develops following repeated exposure to organic antigens, and RA-ILD is a complication of rheumatoid arthritis. We proposed by understanding the relationship between the MUC5B promoter variant, transcriptional regulation, and gene expression in IPF, CHP, and RA-ILD, we will be able to identify the common molecular elements that are critical to the development of UIP. The two critical questions that we plan to address are: 1) what are the common molecular features of UIP, irrespective of clinical context, and 2) does MUC5B promoter variant have a unique molecular signature common to UIP? The hypothesis we plan to test is that the gain-of-function MUC5B promoter variant drives cell-specific chromatin accessibility and gene expression that define UIP. In Aim 1, we will use single nucleus RNA sequencing (snRNA-seq) to identify the cell-specific transcriptional profiles for IPF, CHP, and RA-ILD, and determine the relationship of the common cell-specific transcriptional profiles of UIP to the MUC5B promoter variant. In Aim 2, we will use a combinatorial indexing single nucleus assay for transposase-accessible chromatin (snATAC-seq) to identify the cell-specific chromatin accessibility profiles for IPF, CHP, and RA-ILD, and determine the relationship of the common cell-specific chromatin accessibility profiles of UIP to the MUC5B promoter variant. In Aim 3, we will perform integrative analyses of the MUC5B promoter genotype, snRNA-seq, and snATAC-seq data using single-cell expression QTL, multi-omic and network inference methods to identify UIP-specific gene regulatory networks with key drivers of UIP in specific cell types. In Aim 4, we will validate the transcriptional features that are common to MUC5B-associated UIP by determining the relationship of these key genes to the pathogenic heterogeneity of UIP and relevant in vitro biology. In aggregate, we will characterize regulatory effects of MUC5B on cell-specific transcriptional profiles and networks in UIP, launching investigation of novel pathogenic mechanisms and drug targets for these incurable diseases.

摘要：本研究的总体目标是了解MUC5B启动子如何获得功能