Molecular Determinants of Usual Interstitial Pneumonia (UIP)

普通间质性肺炎 (UIP) 的分子决定因素

基本信息

批准号：
10594554
负责人：
David Albert Schwartz
金额：
$ 71.02万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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/10594554
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 Epithelium 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 Lung Lung diseases MUC5B gene Methods Methylation 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 Structure of parenchyma of lung Testing 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 single nucleus RNA-sequencing transcription factor

项目摘要

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：该提案的总体目标是了解功能获得性 MUC5B 启动子如何变异影响转录调控和基因表达，这对于临床不同类型的常见间质性肺炎（UIP）。 UIP 最初被描述为一个形态实体，但最近已被使用特定的病理学和放射学标准定义。虽然 UIP 是特发性肺病的特征纤维化（IPF），慢性纤维化间质性肺炎的这些病理和放射学模式也与典型的慢性过敏性肺炎 (CHP)、类风湿性关节炎相关的间质性肺病（RA-ILD）、石棉肺和几种药物引起的肺部疾病。 MUC5B 中的功能获得启动子变体 (rs35705950) 是 IPF 的主要危险因素，存在于 >50% 的受影响患者中，并且也已被据报道，它是发生 CHP 和 RA-ILD 的显性遗传风险变异。然而，虽然 IPF 根据定义，CHP 是特发性的，反复接触有机抗原后发生，而 RA-ILD 是一种类风湿性关节炎的并发症。我们通过了解MUC5B之间的关系提出 IPF、CHP 和 RA-ILD 中的启动子变异、转录调控和基因表达，我们将能够确定对 UIP 发展至关重要的常见分子元件。两个关键问题我们计划解决的问题是：1）无论临床情况如何，UIP 的常见分子特征是什么， 2) MUC5B 启动子变体是否具有 UIP 共有的独特分子特征？假设我们计划测试的是功能获得性 MUC5B 启动子变体驱动细胞特异性染色质定义 UIP 的可及性和基因表达。在目标 1 中，我们将使用单核 RNA 测序 (snRNA-seq) 识别 IPF、CHP 和 RA-ILD 的细胞特异性转录谱，并确定 UIP 的常见细胞特异性转录谱与 MUC5B 启动子变体的关系。在目标 2 中，我们将使用组合索引单核测定来检测转座酶可及的染色质 (snATAC-seq) 识别 IPF、CHP 和 RA-ILD 的细胞特异性染色质可及性特征，并确定 UIP 的常见细胞特异性染色质可及性特征与 MUC5B 启动子变体的关系。在目标 3 中，我们将对 MUC5B 启动子基因型、snRNA-seq 和 snATAC-seq 进行综合分析使用单细胞表达QTL、多组学和网络推理方法的数据来识别UIP特异性基因特定细胞类型中 UIP 关键驱动因素的调控网络。在目标 4 中，我们将验证转录通过确定这些关键基因与 MUC5B 相关 UIP 的共同特征 UIP 的致病异质性和相关体外生物学。总的来说，我们将描述监管 MUC5B 对 UIP 中细胞特异性转录谱和网络的影响，启动了新的研究这些疑难杂症的致病机制和药物靶点。