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.

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）和普通变体（22-26）与IPF相关，并且至少占开发风险的40％ 这种疾病。在过去的五年中，我们发现：1）功能获得的MUC5B启动子变体RS35705950 是IPF发展的强大风险因素（22，26-34）； 2）表观遗传机制影响 MUC5b的表达（35）; 3）IPF是一种复杂的遗传疾病，有罕见和常见的变体有助于 该疾病的发展，包括明显的DNA甲基化变化（36）和转录 亚型（37）; 4）MUC5B似乎参与IPF的发病机理（27，38-40）。但是，有 对于MUC5B启动子变体的低渗透性没有明确的解释；而MUC5B的次要等位基因是 IPF出现在杂合或纯合状态（27）中，IPF发生在较少的情况下。 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 通过识别控制MUC5B表达的基因和转录本，并有助于 肺纤维化的发展。为了生成可行的实验模型来追求这一概念，我们 表型在八个用于创建的创始人小鼠菌株中对气管内博来霉素的反应 多样性杂种（DO）小鼠种群（43），发现尽管 MUC5B RNA和MUC5B蛋白表达和博来霉素诱导的肺纤维化，这种关系不是 在八个创始人DO小鼠菌株中保持一致。这些初步发现表明DO鼠标 种群可用于将遗传变异与基因表达相结合，以创建多尺度模型 博来霉素诱导的肺纤维化，然后使用这些知识了解MUC5B诱导的遗传基础 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MUC5B/MUC5B表达有助于发展肺纤维化的风险。在这个项目中， 我们计划表型和​​基因型900小鼠对博来霉素的反应，以鉴定基因 控制MUC5B蛋白表达并有助于肺纤维化的发展（AIM 1），同时也 确定与博来霉素诱导的肺纤维化相关的转录变化（包括MUC5B转录本） （目标2）。然后，我们将确定这些候选基因和小鼠中是否鉴定出的转录变化 暴露于博来霉素可推广到IPF（AIM 3）。这些目标的成功完成将具有广泛的 影响，导致特定的遗传靶标和生物学途径用于设计未来预防的设计， IPF的机械和干预研究。

项目成果

COVID-19: A Time to Reinvest in Our Scientists.

• DOI: 10.1164/rccm.202012-4497le
• 发表时间: 2021-05-01
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Burden M;Flores SC;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

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

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

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。

• DOI: 10.1164/rccm.202109-2219pp
• 发表时间: 2022
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Stancil,IanT;Michalski,JacobE;Schwartz,DavidA
• 通讯作者: Schwartz,DavidA