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

• 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
• 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

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

项目成果

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
• 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

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

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

Methotrexate and rheumatoid arthritis associated interstitial lung disease.

• DOI: 10.1183/13993003.00337-2020
• 发表时间: 2021-03
• 期刊: The European respiratory journal
• 作者: Juge PA;Lee JS;Lau J;Kawano-Dourado L;Rojas Serrano J;Sebastiani M;Koduri G;Matteson E;Bonfiglioli K;Sawamura M;Kairalla R;Cavagna L;Bozzalla Cassione E;Manfredi A;Mejia M;Rodríguez-Henriquez P;González-Pérez MI;Falfán-Valencia R;Buendia-Roldán I;Pérez-Rubio G;Ebstein E;Gazal S;Borie R;Ottaviani S;Kannengiesser C;Wallaert B;Uzunhan Y;Nunes H;Valeyre D;Saidenberg-Kermanac'h N;Boissier MC;Wemeau-Stervinou L;Flipo RM;Marchand-Adam S;Richette P;Allanore Y;Dromer C;Truchetet ME;Richez C;Schaeverbeke T;Lioté H;Thabut G;Deane KD;Solomon JJ;Doyle T;Ryu JH;Rosas I;Holers VM;Boileau C;Debray MP;Porcher R;Schwartz DA;Vassallo R;Crestani B;Dieudé P
• 通讯作者: Dieudé P