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

描述(由申请人提供)：预计总共225个 1998年至2030年期间将出现100万新的结核病病例。结果是 原发感染结核分枝杆菌(MTB)的情况各不相同，在 具有免疫能力的宿主，仅有10%的终生患病风险 临床疾病。结核病易感性的显著差异 免疫能力强的个体之间的关系仍不清楚。中美之间的差异 相似危险因素环境下结核病感染的转归 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，对遗传基因的鉴定 与结核病易感性相关的因素将具有重要的 对控制疾病的影响。 我们使用小鼠感染MTB强毒株的实验模型来 描述控制结核病感染的基因 在有免疫能力的宿主中。我们已经确定并绘制了一个2厘米的间隔 小鼠染色体1是一个新的基因座(Sst1)，它显著地促进了 控制主要在肺部的毒力结核分枝杆菌的生长。对ITS的观察 表型表达表明控制感染的遗传机制 与控制无毒疫苗的结核分枝杆菌不同 牛分支杆菌卡介苗菌株。产生了一组sst1同源近交系 我们建议使用它们(1)通过以下方式分离sst1候选基因 定位克隆；(2)鉴定遗传多态 结核病易感性；(3)鉴定细胞和功能途径 受sst1基因多态性的影响。 拟议的项目将确定 小鼠的sst1，这将在未来允许分离其人 同源基因及其在结核病易感性中的作用分析 人类。对基因决定的运作机制的理解 在肺结核的过程中，肺部的感染会提供新的 对结核病发病机制的见解并提出改进策略 用于治疗和预防这种疾病。

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.