Functional Genetics of COPD

慢性阻塞性肺病的功能遗传学

• 批准号: 8179032
• 负责人: Edwin K Silverman
• 金额: $ 267.3万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-17 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8179032
• 关键词: Functional; Genetics; COPD

PROJECT SUMMARY (See instructions): The overall goal of this PPG is to understand the genetic, genomic, and epigenetic determinants of variable susceptibility to develop COPD. Three COPD susceptibility loci have recently been definitively identified by genome-wide association studies¿¿¿two loci on chromosome 4 (near HHIP and in FAM13A) and one locus on chromosome 15 (a block of genes including IREB2). However, the key genetic determinants in these regions and their functional impact on COPD have not been defined. The three projects In this PPG focus on Genetics (Project 1, PI: Silverman); Gene Expression (Project 2, PI: Choi); and DNA Methylation (Project 3, PI: DeMeo). These projects will build on a substantial existing infrastructure of well-phenotyped study populations, experience in phenotypic characterization of COPD, and an extensive track record of both in vitro and in vivo functional assessment of COPD pathogenesis. There are likely multiple additional COPD susceptibility loci, which need to be discovered. Some of these genetic loci may be influenced primarily by epigenetic alterations (e.g. DNA methylation) instead of, or In addition to, heritable SNP variation. Moreover, the other gene members of the pathways related to these genetic determinants of COPD are unknown, and assessment of gene expression and DNA methylation can likely provide insight into these pathways. Thus, we have included Discovery of additional gene expression and epigenetic influences on COPD susceptibility as a central focus of this PPG. In addition, the actual genetic determinants within the GWAS loci have not been proven. Thus, we have included efforts to localize the key genes within those regions. Multiple approaches will be used to accomplish this goal. Including assessment of genetic association in a population of different genetic ancestry (African Americans from the COPDGene project), analysis of gene expression among genes within GWAS loci, assessment for epigenetic changes of genes within GWAS loci, and assays of long-range gene regulation (e.g. chromosome conformation capture). In addition to Localization of the key determinants, Functional Validation will be required to confirm that specific genes are Involved in COPD pathogenesis and to understand their impact. We will employ both in vitro assessment within lung epithelial and monocyte cell lines (with validation in primary cell types) as well as in vivo assessment in murine models of underexpression (knockout) of the key genes and susceptible vs. resistant Inbred strains which are tested with long-term cigarette smoke exposure. We anticipate that these studies will provide insight into the pathways and mechanisms for COPD susceptibility.

项目总结（见说明）： 本PPG的总体目标是了解COPD易感性可变的遗传、基因组和表观遗传决定因素。最近通过全基因组关联研究确定了三个COPD易感基因座，其中两个基因座位于4号染色体上（靠近HHIP和FAM 13 A），一个基因座位于15号染色体上（包括IREB 2在内的一组基因）。然而，这些区域的关键遗传决定因素及其对COPD的功能影响尚未确定。该PPG中的三个项目侧重于遗传学（项目1，PI：Silverman）;基因表达（项目2，PI：Choi）;和DNA甲基化（项目2，PI：Choi）。 3，PI：DeMeo）.这些项目将建立在良好表型研究人群的大量现有基础设施、COPD表型表征的经验以及COPD发病机制的体外和体内功能评估的广泛记录基础上。可能存在多个额外的COPD易感基因座，需要发现。这些遗传基因座中的一些可能主要受表观遗传改变（例如DNA甲基化）的影响，而不是遗传性SNP变异，或者除了遗传性SNP变异之外。此外，与COPD的这些遗传决定因素相关的途径的其他基因成员是未知的，并且基因表达和DNA甲基化的评估可能提供对这些途径的深入了解。因此，我们将发现其他基因表达和表观遗传学对COPD易感性的影响作为PPG的中心焦点。此外，GWAS基因座内的实际遗传决定因素尚未得到证实。因此，我们已经包括了在这些区域内定位关键基因的努力。将采用多种方法来实现这一目标。包括评估不同遗传血统人群（来自COPDGene项目的非裔美国人）的遗传关联、分析GWAS基因座内基因之间的基因表达、评估GWAS基因座内基因的表观遗传变化以及远程基因调控分析（例如染色体）。构象捕获）。除了定位关键决定因素外，还需要进行功能验证，以确认特定基因参与COPD发病机制并了解其影响。我们将采用肺上皮细胞和单核细胞细胞系（在原代细胞类型中进行验证）的体外评估以及关键基因低表达（敲除）小鼠模型和敏感与耐药近交系（经长期香烟烟雾暴露测试）的体内评估。我们预计这些研究将为COPD易感性的途径和机制提供深入了解。