Role of genetic variation in TGF-beta overactivation in COPD

遗传变异在 COPD 中 TGF-β 过度激活中的作用

• 批准号: 8272179
• 负责人: Stephen L Nishimura
• 金额: $ 57.95万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8272179
• 关键词: 5' Flanking Region; Affinity; African American; Alleles; Architecture; Binding; Biological Assay; Candidate Disease Gene; Caucasians; Caucasoid Race; Cell surface; Cells; Chromatin; Chronic; Chronic Obstructive Airway Disease; DNA; DNA Resequencing; Data; Dendritic Cells; Development; Disease; Enhancers; Epidemiologic Studies; Epithelial Cells; Fibroblasts; Frequencies; Functional RNA; Genes; Genetic; Genetic Epistasis; Genetic Markers; Genetic Variation; Genomics; Genotype; Goals; Haplotypes; Human; In Vitro; Incidence; Integrins; Interleukin-13; Interleukin-4; International; Intervention; Link; Lung; Maps; Measures; Mediator of activation protein; Modeling; Morbidity - disease rate; Mus; Nucleic Acid Regulatory Sequences; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Population; Positioning Attribute; Predisposition; Publishing; Pulmonary Emphysema; Randomized Clinical Trials; Refractory; Regulation; Regulatory Element; Reporter; Respiratory physiology; Risk; Role; Smoker; Smoking; Specimen; Testing; Therapeutic Agents; Transforming Growth Factor beta; Transgenic Mice; Variant; airway remodeling; base; case control; caucasian American; cohort; cytokine; disease phenotype; effective therapy; gene interaction; genetic association; genetic variant; genome-wide; high risk; human MMP14 protein; improved; in vivo; innovation; mortality; mouse model; novel; receptor; success; transcription factor

DESCRIPTION (provided by applicant): Airway remodeling is a critical pathologic component of COPD and is refractory to current therapies. Exacerbations are more frequent in patients with severe COPD, as is airway remodeling, suggesting that airway remodeling and exacerbations are mechanistically linked. Therapies aimed at reversing or stabilizing airway remodeling have the potential to improve lung function and reduce the frequency of exacerbations. There is considerable variability in the reduction in lung function among smokers with similar smoking exposures suggesting that there are genetic differences in susceptibility to airway remodeling in COPD. Our published and preliminary data implicate the integrin ¿8 subunit (ITGB8), which is a major cell surface TGF-¿ receptor regulating the activity and fibroinflammatory effects of TGF-¿, as a novel candidate gene involved in airway remodeling in COPD. Increased expression of ¿v¿8 is seen in airway fibroblasts of human COPD biospecimens, and here we present preliminary genetic epidemiologic studies showing an association of snp rs9791961, which resides in the 5' flanking region near ITGB8, with COPD. The high-risk genotype is associated with increased expression in primary COPD fibroblasts. The integrin ¿v¿8 (expressed in the lung by fibroblasts, dendritic cells and epithelial cells), is a high affinity receptor for the latncy associated peptide (LAP) of TGF-¿, a multifunctional cytokine that must be activated in order to function. Through interactions with LAP, ¿v¿8 is the major activation mechanism of TGF-¿1 (and ¿3) during development and in airway remodeling, in vivo. ITGB8 interacts with a number of genes in the TGF-¿ pathway and is thus positioned at the center of an epistatic circuit regulating the function of TGF-¿ in airway disease. Here we propose the innovative approach of comprehensive discovery of all common ITGB8 genetic variants by sequencing the ITGB8 genomic locus, performing genetic epidemiologic studies, correlation of genetic variants of ITGB8 with increased expression of ITGB8 in human biospecimens, identification and functional analysis of enhancer/repressor regions of ITGB8, and a final test of ITGB8 genetic variants in susceptibility to airway remodeling using humanized BAC transgenic (Tg) mice. Hypothesis: Genetic variation in ITGB8 leads to increased expression of ¿v¿8 and contributes to airway remodeling in COPD. Overall goal: To identify genetic markers for pharmacogenetic targeting of ¿v¿8 in COPD patients. PUBLIC HEALTH RELEVANCE: COPD is a major cause of morbidity and mortality, is increasing in incidence worldwide, and has no know effective therapies. Here, we investigate genetic regulation of ITGB8, a critical mediator of TGF-¿ activity, and a candidate mediator of the lung pathology associated with COPD, as a first step in pharmacogenetic targeting of ITGB8 in COPD.

描述（由申请人提供）：气道重塑是 COPD 的关键病理组成部分，目前的治疗难以治愈。严重 COPD 患者的病情加重更为频繁，气道重塑也是如此，这表明气道重塑和病情加重在机制上是相关的。旨在逆转或稳定气道重塑的治疗有可能改善肺功能并降低病情恶化的频率。吸烟暴露相似的吸烟者肺功能下降存在相当大的差异，这表明慢性阻塞性肺病气道重塑的易感性存在遗传差异。我们发表的初步数据表明，整合素8亚基（ITGB8）是一种主要的细胞表面TGF-β受体，调节TGF-β的活性和纤维炎症效应，是参与COPD气道重塑的新型候选基因。在人类 COPD 生物样本的气道成纤维细胞中观察到 ¿v¿8 的表达增加，在这里我们提出了初步的遗传流行病学研究，显示了位于 ITGB8 附近 5' 侧翼区域的 snp rs9791961 与 COPD 的关联。高风险基因型与原代慢性阻塞性肺病成纤维细胞表达增加有关。整合素 νv 8（在肺中由成纤维细胞、树突细胞和上皮细胞表达）是 TGF-β 潜伏相关肽 (LAP) 的高亲和力受体，TGF-β 是一种多功能细胞因子，必须被激活才能发挥作用。通过与 LAP 相互作用，¿v¿8 是体内发育和气道重塑过程中 TGF-¿1（和 ¿3）的主要激活机制。 ITGB8 与 TGF-¿ 途径中的许多基因相互作用，因此位于调节 TGF-¿ 在气道疾病中的功能的上位回路的中心。在这里，我们提出了通过对ITGB8基因组位点进行测序、进行遗传流行病学研究、ITGB8遗传变异与人类生物样本中ITGB8表达增加的相关性、ITGB8增强子/阻遏子区域的鉴定和功能分析以及ITGB8遗传的最终测试来全面发现所有常见ITGB8遗传变异的创新方法。 使用人源化 BAC 转基因 (Tg) 小鼠研究气道重塑易感性的变异。假设：ITGB8 的遗传变异导致 ¿v¿8 的表达增加，并有助于 COPD 的气道重塑。总体目标：确定 COPD 患者中 ¿v¿8 药物遗传学靶向的遗传标记。 公共卫生相关性：慢性阻塞性肺病是发病和死亡的主要原因，其发病率在世界范围内不断增加，并且尚无有效的治疗方法。在这里，我们研究了 ITGB8 的基因调控，ITGB8 是 TGF-β 活性的关键介质，也是与 COPD 相关的肺部病理学的候选介质，作为 COPD 中 ITGB8 药物遗传学靶向的第一步。