Genetics of Asthma and COPD

哮喘和慢性阻塞性肺病的遗传学

• 批准号: 7218219
• 负责人: STEVEN D SHAPIRO
• 金额: $ 84.8万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7218219
• 关键词: Affect; Animal Model; Asthma; Bioinformatics; Candidate Disease Gene; Chronic Disease; Chronic Obstructive Airway Disease; Chronic Obstructive Asthma; Cigarette; Classification; Communities; Complex; Computer Simulation; Data; Databases; Deposition; Development; Disease; Evaluation; Exposure to; Fibrosis; Future; Gene Expression; Genes; Genetic; Genetic Crosses; Genetic Determinism; Genetic Polymorphism; Genetic Research; Genetically Engineered Mouse; Genome; Genomics; Haplotypes; Human; Inbred Mouse; Inbred Strain; Inbred Strains Mice; Inflammation; Investigation; Lead; Location; Lung; Lung diseases; Maps; Measurement; Measures; Modeling; Morphology; Mouse Strains; Mus; Pathologic; Phenotype; Physiological; Population; Positioning Attribute; Proteomics; Protocols documentation; Pulmonary Emphysema; Quantitative Trait Loci; Research; Research Personnel; Risk; Role; Running; Silicon Dioxide; Smoke; Smoking; Surveys; System; Techniques; Testing; Work; airway hyperresponsiveness; airway remodeling; base; cigarette smoke-induced; cigarette smoking; cigarette smoking; cohort; cost; cost effective; data mining; disease phenotype; human disease; methacholine; programs; response; tool

Asthma and Chronic Obstructive Pulmonary Disease (COPD) are the two most common chronic diseases of the airways. Understanding the genetic basisfor these diseaseswill allow us to dissect pathogenetic mechanisms, assess risk, and ultimately lead to individualized therapy. Finding disease genes in animal models of complex human diseases is easier and more cost effective then relying only upon investigation in well characterized human cohorts. Significant variability across mouse strains is observed for both native airways responsiveness and the development of smoke-induced COPD, suggesting a role for genetic determinants of these phenotypes in the mouse. However, in the fields of asthma and COPDresearch, there is a lack of comprehensive strain surveysand too few animalQTL studies to take advantage of the latest genomic and proteomic research that have been developed and utilized to find QTL in other complex human disease. In this project, we will identify genes that influence airway hyperresponsiveness (AHR) and cigarette smoke-induced COPD in mice by surveying36 inbred mousestrains for AHR and COPD. Subsequently, we will employ in silica computationalQTL analysisto detect regions that containAHR and COPD genes, particularly focusing on those genomic regions that influence both AHR and COPD. Based on the computational QTL analysis, we next will select parental strains and carry out actual QTL crosses. Finally, once the QTL have been identified, we will focus on those that are located in positions homologous to human QTL and use several data mining techniques and additionalgenetic crossesto find candidate genes. These candidate genes will be tested for associationin human populations in Projects 1 (asthma) and 2(COPD), thus combining the strengths of the human and mouse systems. We anticipate that providing this strain survey information to the scientific communitywill stimulate additional research in models of asthma and COPD, and will acceleratethe finding of asthma and COPDgenes. Becauseof the high homology between human and mouse locationsfor QTL for commondiseases, including asthma,we hypothesize that a coordinated approach to gene finding using both the animal model and human populations will be more cost-effectiveand successful,and will provide an important infrastructurefor the continuation of genetic research in asthmaandCOPD.

哮喘和慢性阻塞性肺疾病（COPD）是两种最常见的慢性疾病 呼吸道。了解这些疾病的遗传基础，这将使我们能够剖析病原体 机制，评估风险并最终导致个性化治疗。在动物中找到疾病基因 复杂人类疾病的模型更容易，更具成本效益，而不是仅依靠调查 人类人群的特征很好。两种天然都观察到小鼠菌株之间的显着差异 气道响应能力和烟雾引起的COPD的发展，这表明了遗传的作用 这些表型在小鼠中的决定因素。但是，在哮喘和Copdresearch领域 缺乏全面的应变调查，而动物QTL的研究太少了，无法利用 已开发和利用的最新基因组和蛋白质组学研究在其他复合物中找到QTL 人类疾病。在这个项目中，我们将确定影响气道高反应性（AHR）和 香烟烟雾引起的小鼠COPD通过测量AHR和COPD的近交鼠虫测量。 随后，我们将在二氧化硅computitationqtl Analysisto中检测到包含和 COPD基因，特别是专注于影响AHR和COPD的基因组区域。基于 计算QTL分析，我们接下来将选择父母菌株并执行实际的QTL杂交。 最后，一旦确定了QTL，我们将专注于位于同源位置的QTL 到人类QTL并使用多种数据挖掘技术和额外的Crossesto查找候选者 基因。这些候选基因将在项目1（哮喘）中测试人类的关联人群 和2（COPD），因此结合了人类和小鼠系统的强度。我们预计提供 对科学社区的应变调查信息将刺激在模型中的其他研究 哮喘和COPD，并将加速发现哮喘和Copdgenes。因为高 人类和小鼠位置之间的同源性QTL用于共享，包括哮喘，我们 假设使用动物模型和人类的一种协调的基因发现方法 人口将取得更大的成本效益成功，并为其提供重要的基础设施 哮喘和碱性研究的延续。