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Genes and Transcripts that Interact with MUC5B in Pulmonary Fibrosis

肺纤维化中与 MUC5B 相互作用的基因和转录本

基本信息

批准号：
10402929
负责人：
David E. Clouthier
金额：
$ 67.79万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10402929
关键词：
Address Affect Alleles Biological Bleomycin Candidate Disease Gene Complex Control Locus Cyst DNA DNA Methylation Data Development Disease Distal Epigenetic Process Epithelial Epithelial Cells Etiology Experimental Models Exposure to Fibrosis Future Gene Expression Gene Expression Profiling General Population Genes Genetic Genetic Diseases Genetic Transcription Genetic Variation Genotype Goals Human Human Genetics Impairment Intervention Studies Irrigation Knowledge Lead Lung MUC5B gene Minor Mouse Strains Muc5B protein Mucins Mucociliary Clearance Mucolytics Mus Mutation Pathogenesis Pathway interactions Penetrance Peripheral Phenotype Population Preventive Production Pulmonary Fibrosis Pulmonary Surfactant-Associated Protein C Quantitative Trait Loci RNA Research Resolution Resources Risk Risk Factors Smoking Structure of parenchyma of lung Targeted Resequencing Transcript Variant alveolar epithelium base cell type design disorder risk endoplasmic reticulum stress gain of function genome sequencing genome wide association study genome-wide genomic locus idiopathic pulmonary fibrosis indium-bleomycin lung development mortality multi-scale modeling novel overexpression promoter protein expression response risk variant transcriptome sequencing transcriptomics whole genome

项目摘要

ABSTRACT The overall goal of our proposed research is to identify genes and transcripts associated with MUC5B expression that contribute to the development of idiopathic pulmonary fibrosis (IPF). Rare mutations (16- 21) and common variants (22-26) are associated with IPF and account for at least 40% of the risk of developing this disease. In the past 5 years, we have found that: 1) a gain-of-function MUC5B promoter variant rs35705950 is the strongest risk factor for the development of IPF (22, 26-34); 2) epigenetic mechanisms affect the expression of MUC5B (35); 3) IPF is a complex genetic disease with rare and common variants contributing to the development of this disease, including pronounced changes in DNA methylation (36) and transcriptional subtypes (37); and 4) MUC5B appears to be involved in the pathogenesis of IPF (27, 38-40). However, there is no clear explanation for the low penetrance of the MUC5B promoter variant; while the minor allele of MUC5B is present in the heterozygous or homozygous state in ≈19% of the general population (27), IPF occurs in far less than 1% of the population (41, 42). These observations lead us to postulate that the etiology of IPF will best be understood by identifying the genes and transcripts that control MUC5B expression and contribute to the development of pulmonary fibrosis. To generate a feasible experimental model to pursue this concept, we phenotyped the response to intratracheal bleomycin in the eight founder mouse strains that were used to create the Diversity Outbred (DO) mouse population (43) and found that although there is a clear relationship between Muc5b RNA and MUC5B protein expression and bleomycin-induced lung fibrosis, this relationship is not consistent across the eight founder DO mouse strains. These preliminary findings suggest that the DO mouse population can be used to integrate genetic variation with gene expression to create multi-scale models of bleomycin-induced lung fibrosis and then use this knowledge to understand the genetic basis of MUC5B-induced IPF. Based on these observations, we hypothesize that genes and transcripts that control bleomycin- induced Muc5b/MUC5B expression contribute to the risk of developing pulmonary fibrosis. In this project, we plan to phenotype and genotype 900 DO mice for their response to bleomycin to identify the genes that control MUC5B protein expression and contribute to the development of lung fibrosis (Aim 1), while also identifying transcriptional changes (including Muc5b transcript) associated with bleomycin-induced lung fibrosis (Aim 2). We will then determine whether these candidate genes and transcriptional changes identified in mice exposed to bleomycin are generalizable to IPF (Aim 3). The successful completion of these Aims will have broad impact, resulting in specific genetic targets and biologic pathways for use in the design of future preventive, mechanistic, and intervention studies of IPF.

抽象的我们提出的研究的总体目标是识别与 MUC5B 相关的基因和转录本有助于特发性肺纤维化（IPF）发展的表达。罕见突变（16- 21) 和常见变异 (22-26) 与 IPF 相关，并且至少占 40% 的罹患 IPF 的风险这种病。在过去的5年里，我们发现：1）一个获得功能的MUC5B启动子变体rs35705950 是发生 IPF 的最强风险因素 (22, 26-34)； 2）表观遗传机制影响 MUC5B 的表达 (35)； 3) IPF 是一种复杂的遗传性疾病，具有罕见和常见的变异，导致这种疾病的发展，包括 DNA 甲基化 (36) 和转录的显着变化亚型 (37)； 4) MUC5B 似乎参与 IPF 的发病机制 (27, 38-40)。然而，有对于MUC5B启动子变体的低外显率没有明确的解释；而 MUC5B 的次要等位基因是约 19% 的普通人群以杂合或纯合状态存在 (27)，IPF 的发生率要低得多少于 1% 的人口 (41, 42)。这些观察结果使我们推测 IPF 的病因最好是通过识别控制 MUC5B 表达并有助于肺纤维化的发展。为了生成一个可行的实验模型来追求这个概念，我们对用于创建的八个创始小鼠品系的气管内博来霉素的反应进行了表型分析多样性远交 (DO) 小鼠群体 (43) 并发现，尽管之间存在明显的关系 Muc5b RNA和MUC5B蛋白表达与博莱霉素诱导的肺纤维化关系不大八个创始人 DO 小鼠品系的一致性。这些初步发现表明 DO 小鼠群体可用于将遗传变异与基因表达整合起来，以创建多尺度模型博来霉素诱导的肺纤维化，然后利用这些知识来了解 MUC5B 诱导的肺纤维化的遗传基础特发性肺纤维化。基于这些观察，我们假设控制博莱霉素的基因和转录本诱导的 Muc5b/MUC5B 表达会增加发生肺纤维化的风险。在这个项目中，我们计划对 900 只 DO 小鼠进行表型和基因型分析，了解它们对博来霉素的反应，以确定影响控制 MUC5B 蛋白表达并促进肺纤维化的发展（目标 1），同时还鉴定与博来霉素诱导的肺纤维化相关的转录变化（包括 Muc5b 转录物）（目标 2）。然后我们将确定这些候选基因和转录变化是否在小鼠中发现接触博来霉素可推广至 IPF（目标 3）。这些目标的成功实现将产生广泛的影响影响，产生特定的遗传目标和生物途径，用于设计未来的预防、 IPF的机制和干预研究。