Role of genetic variation in TGF-beta overactivation in COPD

描述(由申请人提供)：气道重塑是COPD的关键病理成分，对目前的治疗方法难以奏效。重度COPD患者的恶化更常见，气道重塑也是如此，这表明气道重塑和恶化在机械上是有联系的。旨在逆转或稳定气道重塑的治疗方法有可能改善肺功能，减少恶化的频率。在吸烟环境相似的吸烟者中，肺功能的降低有相当大的差异性，这表明COPD患者对呼吸道重塑的易感性存在遗传差异。我们已发表的初步数据表明，整合素β8亚单位(ITGB8)是调节转化生长因子β的活性和纤维炎症效应的主要细胞表面受体，是参与COPD气道重塑的一个新的候选基因。在人类COPD生物样本的呼吸道成纤维细胞中发现V8的表达增加，在这里，我们提出了初步的遗传流行病学研究，表明位于ITGB8附近的5‘侧翼区域的SNP rs9791961与COPD有关。高危基因与原代COPD成纤维细胞表达增加有关。整合素是一种与转化生长因子-β潜伏期相关肽(LAP)的高亲和力受体，它是一种多功能细胞因子，必须被激活才能发挥作用。在体内，通过与LAP的相互作用，βv-8是转化生长因子-β1(和β3)在发育和气道重塑中的主要激活机制。ITGB8与转化生长因子-β途径中的许多基因相互作用，因此位于调节转化生长因子-β在呼吸道疾病中功能的上位性回路的中心。在这里，我们提出了一种创新的方法，通过对ITGB8基因组基因座进行测序，进行遗传流行病学研究，研究ITGB8基因变异与ITGB8在人类生物标本中表达增加的相关性，鉴定ITGB8的增强/抑制区并进行功能分析，以及使用人源化BAC转基因(TG)小鼠对ITGB8基因变异的易感性进行最终测试，从而全面发现所有常见的ITGB8基因变异。假设：ITGB8基因变异导致V8表达增加，并参与COPD的气道重塑。总体目标：确定COPD患者药物遗传学靶向的遗传标记。

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.