New locus controlling suscept. to TB: genetics & funct.

新的位点控制敏感度。

基本信息

批准号：
6897926
负责人：
Igor Kramnik
金额：
$ 40.45万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-30 至 2006-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by the applicant): It is projected that a total of 225 million new cases of tuberculosis will occur between 1998 and 2030. The outcome of primary infection with Mycobacterium tuberculosis (MTB) varies and, in immunocompetent hosts, imparts only a 10 percent lifetime risk of developing clinical disease. The significant variation in tuberculosis susceptibility among immunocompetent individuals remains unexplained. Differences in the outcome of tuberculosis infection in the setting of similar risk factors support a significant role of the host genetic background in predisposition to progression towards clinical disease. Therefore, identification of genetic factors associated with susceptibility to tuberculosis will have important implications for controlling the disease. We use a mouse experimental model of infection with virulent strain of MTB to characterize genes that are responsible for control of tuberculosis infection in immunocompetent hosts. We have identified and mapped to a 2 cM interval on mouse chromosome 1 a novel locus (sst1) that significantly contributes to control of growth of virulent MTB primarily in the lungs. Observations on its phenotypic expression demonstrate that genetic mechanisms controlling infection with virulent MTB are distinct from those that control an avirulent vaccine strain of M bovis BCG. Having generated a set of sst1-congenic inbred strains of mice, we propose to use them (1) to isolate the sst1-candidate genes by positional cloning; (2) to identify genetic polymorphism responsible for tuberculosis susceptibility; (3) to identify cells and functional pathways affected by the sst1 polymorphism. The proposed project will identify the nature and mechanism of action of the sst1 in mice, which in the future should permit isolation of its human homologue and the analysis of its role in tuberculosis susceptibility in humans. The understanding of genetically determined mechanisms that operate during the course of tuberculosis infection in the lung will provide new insights into the pathogenesis of tuberculosis and suggest improved strategies for treatment and prevention of the disease.

描述（由申请人提供）：预计总共225 数百万新的结核病病例将在1998年至2030年之间发生。结果结核分枝杆菌（MTB）的原发性感染变化，在免疫能力的宿主仅赋予开发10％的终身风险临床疾病。结核病敏感性的显着差异在免疫能力的个体中，仍然无法解释。差异结核病感染的结果在相似的风险因素的情况下支持宿主遗传背景在易感性中的重要作用向临床疾病的发展。因此，遗传的鉴定与结核病易感性相关的因素将具有重要的控制疾病的影响。我们使用MTB毒性应变的小鼠感染模型表征负责控制结核病感染的基因在免疫能力的宿主中。我们已经确定并映射到2 cm的间隔小鼠染色体1一个新型基因座（SST1），显着有助于控制有毒MTB的生长主要是在肺中。观察到它表型表达表明控制感染的遗传机制用强毒的MTB与控制无毒疫苗的MTB不同 M BOVIS BCG的菌株。产生了一组SST1-繁殖的近交菌株在小鼠中，我们建议使用它们（1）通过位置克隆；（2）确定负责的遗传多态性结核病敏感性；（3）识别细胞和功能途径受SST1多态性的影响。拟议的项目将确定行动的性质和机制在将来应该允许隔离人类的小鼠中的SST1 同源物及其在结核病敏感性中的作用分析人类。对运作的遗传确定机制的理解在结核病感染过程中，肺部将提供新的洞悉结核病的发病机理，并提出改进的策略用于治疗和预防疾病。