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

描述（由申请人提供）：预计共有225个 在1998年至2030年期间，将有100万新的肺结核病例。成果 结核分枝杆菌（MTB）的原发感染率不同， 免疫活性宿主，只赋予10%的终生风险， 临床疾病结核病易感性的显著变化 免疫功能正常的个体之间的差异仍然无法解释。差异 在相似危险因素的背景下结核感染的结局 支持宿主遗传背景在易感性中的重要作用， 向临床疾病发展。因此，鉴定遗传 与结核病易感性相关的因素将具有重要意义 对控制疾病的影响。 我们用结核分枝杆菌强毒株感染小鼠实验模型， 表征负责控制结核病感染的基因 在免疫活性宿主中。我们已经确定并映射到一个2厘米的间隔上， 小鼠1号染色体一个新的基因座（sst 1），它显著地促进了 控制毒性MTB主要在肺中的生长。关于其 表型表达表明控制感染的遗传机制 与控制无毒疫苗的那些不同 牛分枝杆菌BCG菌株。产生了一套sst 1同源的近交系， 的小鼠，我们建议使用它们（1）分离sst 1候选基因， 定位克隆;（2）确定遗传多态性负责 结核易感性;（3）确定细胞和功能途径 受SST 1多态性的影响。 拟议的项目将确定 sst 1在小鼠中，这在未来应该允许分离其人类 同源物及其在结核病易感性中的作用分析 人类对基因决定的机制的理解， 在肺结核感染的过程中， 深入了解结核病的发病机制，并提出改进的策略 用于治疗和预防疾病。

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.