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

• 批准号: 7968946
• 负责人: Lawrence C Brody
• 金额: $ 55.94万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 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/7968946
• 关键词: Asthma; Childhood; Collaborations; Dermatophagoides Antigens; Drug Delivery Systems; Environmental Exposure; Exhibits; Extrinsic asthma; Genes; Genetic Predisposition to Disease; Genetic Variation; Homologous Gene; House Dust Mite Allergens; Human; Inbred Strain; Individual; Inflammation; Laboratories; Laboratory mice; Maps; Measures; Mediating; Mucous body substance; Mus; North Carolina; Onset of illness; Peptide Hydrolases; Phenotype; Play; Population; Predisposition; Preventive; Production; Quantitative Trait Loci; Respiratory physiology; Role; Structure; Testing; Time; Universities; airway hyperresponsiveness; airway inflammation; design; gene environment interaction; mouse model; population based; pyroglyphid; response

We have 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. In order to identify genes that mediate susceptibility to these two phenotypes, we are conducting a large quantitative trait locus (QTL) mapping project using a newly establishing population of genetically diverse mice known as the Collaborative Cross (CC). Mice from the CC are derived from an eight-way cross of common (A/J, C57BL/6J, 129/SvImJ, NOD/ShILtJ and NZO/HILtJ) and wild-derived (WSB/EiJ, PWK/PhJ and CAST/EiJ) inbred strains. The CC was designed to capture maximal genetic diversity of inbred strains and at the same time minimize the effects of population structure, thereby overcoming many of the limitations of previous mapping approaches. Thus far, we have phenotyped more than 150 mice and have made three notable observations: (1) these mice exhibit an incredible range of asthma phenotype diversity, (2) baseline lung function is strongly correlated with lung function after Derp1 challenge, and (3) the degree of airway inflammation caused by Derp1 does not correlate with impaired lung function. During the next year, we plan to finish phenotyping all CC strains, then map the QTLs in collaboration with colleagues at the University of North Carolina and the Jackson Laboratory. Once QTL have been identified, we plan to test the role of human homologs in population-based studies of allergic asthma through collaborations that are already underway.

我们已经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。为了鉴定介导对这两种表型的敏感性的基因，我们使用新建立的遗传多样性小鼠的种群进行了大量的定量性状基因座（QTL）映射项目，称为协作交叉（CC）。来自CC的小鼠衍生自共同的八路十字（A/J，C57BL/6J，129/SVIMJ，NOD/SHILTJ和NZO/HILTJ）和野生衍生（WSB/EIJ，PWK/PWK/PHJ和Cast/Eij）。 CC旨在捕获近交菌株的最大遗传多样性，同时最大程度地减少了种群结构的影响，从而克服了以前的映射方法的许多局限性。 Thus far, we have phenotyped more than 150 mice and have made three notable observations: (1) these mice exhibit an incredible range of asthma phenotype diversity, (2) baseline lung function is strongly correlated with lung function after Derp1 challenge, and (3) the degree of airway inflammation caused by Derp1 does not correlate with impaired lung function. 在第二年，我们计划完成所有CC菌株的表型，然后与北卡罗来纳大学和杰克逊实验室的同事合作绘制QTL。一旦确定了QTL，我们计划通过已经进行的协作来测试人类同源物在基于人群的过敏性哮喘研究中的作用。