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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

基本信息

批准号：
8444421
负责人：
Stephen L Nishimura
金额：
$ 48.35万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/8444421
关键词：
5&apos 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 risk variant success transcription factor

项目摘要

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.

描述（由申请人提供）：气道重塑是COPD的重要病理组成部分，目前的治疗方法难以治疗。急性加重在重度COPD患者中更常见，气道重塑也是如此，这表明气道重塑和急性加重在机制上相关。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急性加重的频率。在吸烟暴露相似的吸烟者中，肺功能降低存在相当大的差异，这表明在COPD气道重塑的易感性方面存在遗传差异。我们发表的和初步的数据表明，整合素8亚基（ITGB 8），这是一个主要的细胞表面TGF-β受体调节TGF-β的活性和纤维炎症效应，作为一个新的候选基因参与气道重塑在COPD。增加表达量v？8在人COPD生物标本的气道成纤维细胞中可见，在这里我们提出了初步的遗传流行病学研究，显示位于ITGB 8附近的5'侧翼区的snp rs 9791961与COPD相关。高风险基因型与原发性COPD成纤维细胞中表达增加相关。整合素v？8（在肺中由成纤维细胞、树突状细胞和上皮细胞表达）是TGF-β的潜伏相关肽（latncy associated peptide，LPS）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功能。通过与TGF-β相互作用，在体内发育和气道重塑过程中，TGF-β 8是TGF-β 1（和TGF-β 3）的主要激活机制。ITGB 8与TGF-β通路中的许多基因相互作用，因此位于调节气道疾病中TGF-β功能的上位回路的中心。在这里，我们提出了全面发现所有常见ITGB 8遗传变异的创新方法，通过对ITGB 8基因组位点进行测序，进行遗传流行病学研究，将ITGB 8的遗传变异与人类生物标本中ITGB 8表达增加相关，鉴定和功能分析ITGB 8的增强子/阻遏子区域，以及使用人源化BAC转基因（Tg）小鼠对ITGB 8遗传变体对气道重塑的易感性进行最终测试。假设：ITGB 8的遗传变异导致<$v <$8表达增加，并有助于COPD的气道重塑。总体目标：确定COPD患者中<$v <$8药物遗传学靶向的遗传标志物。