Gene-environment interactions in asthma in mice and humans

小鼠和人类哮喘中基因与环境的相互作用

基本信息

批准号：
8350015
负责人：
FRANCIS S. COLLINS
金额：
$ 64.68万
依托单位：
NATIONAL HUMAN GENOME RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8350015
关键词：
Asthma Candidate Disease Gene Childhood Chromosomes, Human, Pair 11 Chromosomes, Human, Pair 17 Chromosomes, Human, Pair 2 Collaborations Data Dermatophagoides Antigens Dermatophagoides pteronyssinus antigen p 1 Drug Delivery Systems Environmental Exposure Extrinsic asthma Genes Genetic Genetic Predisposition to Disease Genetic Variation Genotype Homologous Gene House Dust Mite Allergens Human Inbred Strains Mice Individual Inflammation Laboratory mice Lung Lavage Fluid Measures Modeling Mucous body substance Mus Onset of illness Peptide Hydrolases Phenotype Play Population Predisposition Preventive Production Quantitative Trait Loci Role Serum Testing airway hyperresponsiveness airway inflammation density eosinophil gene environment interaction genome sequencing macrophage mouse model neutrophil population based pyroglyphid response

项目摘要

We first established a mouse model of dust mite-induced asthma that recapitulates the key features of human asthma, namely airway hyper-responsiveness, inflammation, and mucus production. We then applied this model to a newly established population of mice known as the Collaborative Cross (CC). This population captures the more than 95% of the genetic diversity present in all inbred strains of mice. This genetic and resulting phenotypic diversity greatly enhances the power to identify quantitative trait loci (QTL). We phenotyped more than 150 mice and genotyped the mice using a high-density Affymetrix array. Using these data, we identified QTL for airway inflammation, specifically the numbers of macrophages (Chromosome (Chr) 17), eosinophils (Chr 11), and neutrophils (Chr 2) in lung lavage fluid. We also identified a QTL for serum IgG2b.We are currently refining these QTL to identify candidate genes using conditional correlation and additional genome sequence data. We plan to test the role of human homologs of the candidate genes we identify in the mouse in human population-based studies of allergic asthma through collaborations that are already underway with Drs. Cookson and Postma.

我们首先建立了一种尘螨诱导的哮喘的小鼠模型，该模型概括了人类哮喘的关键特征，即气道高反应性，炎症和粘液产生。然后，我们将该模型应用于新成立的小鼠人群，称为协作交叉（CC）。该人群捕获了所有近交菌株中存在的遗传多样性的95％以上。这种遗传和由此产生的表型多样性极大地增强了鉴定定量性状基因座（QTL）的能力。我们使用高密度的Affymetrix阵列进行了150多只小鼠的表型，并对小鼠进行了基因分型。使用这些数据，我们确定了气道炎症的QTL，特别是巨噬细胞的数量（染色体（CHR）17），嗜酸性粒细胞（CHR 11）和肺灌洗液中的中性粒细胞（CHR 2）。我们还确定了一个QTL 血清IgG2B。我们目前正在精炼这些QTL，以使用条件相关性和其他基因组序列数据来识别候选基因。我们计划通过已经与DRS正在进行的协作中测试我们在小鼠中鉴定的候选基因的人类同源物的作用。库克森和波斯特玛。