Role of genetic variation in TGF-beta overactivation in COPD

描述（由申请人提供）：气道重塑是COPD的关键病理组成部分，目前的治疗方法难以治愈。严重COPD患者的加重更为频繁，气道重塑也是如此，这表明气道重塑和加重存在机制联系。旨在逆转或稳定气道重塑的治疗具有改善肺功能和减少急性发作频率的潜力。在吸烟暴露程度相似的吸烟者中，肺功能的降低存在相当大的差异，这表明COPD患者对气道重塑的易感性存在遗传差异。我们发表的和初步的数据表明，整合素8亚基（ITGB8）是一个新的候选基因，它是一个主要的细胞表面TGF-¿受体，调节TGF-¿的活性和纤维炎症作用，参与COPD气道重塑。在人类COPD生物标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snp rs9791961与COPD相关，该snp位于ITGB8附近的5'侧翼区域。高危基因型与原发性COPD成纤维细胞表达增加相关。整合素8（在肺中由成纤维细胞、树突状细胞和上皮细胞表达）是TGF-的潜伏期相关肽（LAP）的高亲和力受体，TGF-是一种必须激活才能发挥作用的多功能细胞因子。在体内，通过与LAP的相互作用，¿v¿8是TGF-¿1（和¿3）在发育和气道重塑过程中的主要激活机制。ITGB8与TGF-¿通路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。在此，我们提出了一种创新的方法，即通过对ITGB8基因组位点进行测序，进行遗传流行病学研究，研究ITGB8遗传变异与人类生物标本中ITGB8表达增加的相关性，鉴定ITGB8增强子/抑制子区域并进行功能分析，最后使用人源化BAC转基因（Tg）小鼠测试ITGB8遗传变异与气道重塑易感性的关系，从而全面发现所有常见的ITGB8遗传变异。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.