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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：
10611514
负责人：
David E. Clouthier
金额：
$ 73.77万
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 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10611514
关键词：
Address Affect Alleles Biological Bleomycin Candidate Disease Gene Cell Line Complex Control Locus Cyst DNA DNA Methylation Data Development Disease Distal Epigenetic Process Epithelial Cells Epithelium Etiology Experimental Models Exposure to Fibrosis Future Gene Expression Gene Expression Profiling General Population Genes Genetic Genetic Diseases Genetic Transcription Genetic Variation Genotype Goals Heterozygote Human Human Genetics Impairment Intervention Studies Irrigation Knowledge Lung MUC5B gene Maps 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 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.

摘要我们研究的总体目标是鉴定与MUC 5 B相关的基因和转录本表达，导致特发性肺纤维化（IPF）的发展。罕见突变（16- 21)和常见变异（22-26）与IPF相关，占IPF发展风险的至少40%，这种疾病。在过去的5年中，我们发现：1）MUC 5 B启动子功能获得性变体rs35705950 是IPF发展的最强风险因素（22，26-34）; 2）表观遗传机制影响 MUC 5 B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，有助于这种疾病的发展，包括DNA甲基化（36）和转录的显著变化亚型（37）;和4）MUC 5 B似乎参与IPF的发病机制（27，38-40）。不过有 MUC 5 B启动子变异的低等位基因率没有明确的解释;而MUC 5 B的次要等位基因是 IPF在一般人群中以杂合或纯合状态存在（27），超过1%的人口（41，42）。这些观察结果使我们假设IPF的病因最好是通过鉴定控制MUC 5 B表达并促进MUC 5 B表达的基因和转录本，肺纤维化的发展。为了产生一个可行的实验模型来追求这个概念，我们表型分析了八种用于建立小鼠模型的创始小鼠品系对气管内博莱霉素的反应， Diversity Outbred（DO）小鼠种群（43），发现尽管 Muc 5 b RNA和MUC 5 B蛋白表达与博莱霉素诱导的肺纤维化之间，这种关系是不相关的在八个创始人DO小鼠品系中一致。这些初步发现表明，群体可以用来整合遗传变异与基因表达，以创建多尺度模型，博来霉素诱导的肺纤维化，然后使用这些知识来了解MUC 5 B诱导的肺纤维化的遗传基础。 IPF。基于这些观察，我们假设控制博来霉素的基因和转录本- 诱导的Muc 5 b/MUC 5 B表达有助于发生肺纤维化的风险。在本项目中，我们计划对900只DO小鼠进行表型和基因分型，以确定它们对博来霉素的反应，控制MUC 5 B蛋白表达并促进肺纤维化的发展（目的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Muc 5 b转录物） (Aim 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确定暴露于博来霉素的患者可推广至IPF（目的3）。这些目标的成功实现将具有广泛的影响，产生特定的遗传靶点和生物途径，用于设计未来的预防措施，机制和干预研究。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

From ARDS to pulmonary fibrosis: the next phase of the COVID-19 pandemic?

DOI：
10.1016/j.trsl.2021.09.001
发表时间：
2022-03
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
0
作者：
Michalski JE;Kurche JS;Schwartz DA
通讯作者：
Schwartz DA

Molecular markers of telomere dysfunction and senescence are common findings in the usual interstitial pneumonia pattern of lung fibrosis.

DOI：
10.1111/his.14334
发表时间：
2021-07
期刊：
Histopathology
影响因子：
6.4
作者：
Lee JS;La J;Aziz S;Dobrinskikh E;Brownell R;Jones KD;Achtar-Zadeh N;Green G;Elicker BM;Golden JA;Matthay MA;Kukreja J;Schwartz DA;Wolters PJ
通讯作者：
Wolters PJ

Incidence and Progression of Fibrotic Lung Disease in an At-Risk Cohort.

高危人群中纤维化肺病的发病率和进展。

DOI：
10.1164/rccm.202206-1075oc
发表时间：
2023
期刊：
American journal of respiratory and critical care medicine
影响因子：
24.7
作者：
Steele,MarkP;Peljto,AnnaL;Mathai,SusanK;Humphries,Stephen;Bang,TamiJ;Oh,Andrea;Teague,Shawn;Cicchetti,Giuseppe;Sigakis,Christopher;Kropski,JonathanA;Loyd,JamesE;Blackwell,TimothyS;Brown,KevinK;Schwarz,MarvinI;Warren,R
通讯作者：
Warren,R

Aberrant Multiciliogenesis in Idiopathic Pulmonary Fibrosis.

特发性肺纤维化中的异常多纤毛发生。

DOI：
10.1165/rcmb.2021-0554oc
发表时间：
2022
期刊：
American journal of respiratory cell and molecular biology
影响因子：
6.4
作者：
Kim,Eunjoo;Mathai,SusanK;Stancil,IanT;Ma,Xiaoqian;Hernandez-Gutierrez,Ashley;Becerra,JessicaN;Marrero-Torres,Emilette;Hennessy,CorinneE;Hatakka,Kristina;Wartchow,EricP;Estrella,Alani;Huber,JonathanP;Cardwell,JonathanH;Burn
通讯作者：
Burn

An Airway-Centric View of Idiopathic Pulmonary Fibrosis.

特发性肺纤维化的以气道为中心的观点。