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.

我们已经建立了一个小鼠模型的尘螨诱导的哮喘，概括了人类哮喘的关键特征，即气道高反应性，炎症和粘液的生产。为了确定介导这两种表型易感性的基因，我们正在进行一个大型的数量性状基因座（QTL）定位项目，使用一个新建立的遗传多样性小鼠群体，称为协作交叉（CC）。来自CC的小鼠衍生自常见（A/J、C57 BL/6 J、129/SvImJ、NOD/ShILtJ和NZO/HILtJ）和野生衍生（WSB/EiJ、PWK/PhJ和CAST/EiJ）近交系的八向杂交。CC的目的是捕捉最大的遗传多样性的近交系，并在同一时间，最大限度地减少人口结构的影响，从而克服了许多以前的定位方法的局限性。到目前为止，我们已经对150多只小鼠进行了表型分析，并进行了三个值得注意的观察：（1）这些小鼠表现出令人难以置信的哮喘表型多样性，（2）基线肺功能与Derp 1激发后的肺功能密切相关，（3）Derp 1引起的气道炎症程度与肺功能受损无关。 明年，我们计划完成所有CC菌株的表型分析，然后与北卡罗来纳州大学和杰克逊实验室的同事合作绘制QTL图谱。一旦QTL被确定，我们计划通过已经在进行的合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。