Predicting tuberculosis outcomes using genotypic and biomarker signatures

项目摘要/摘要 结核病是由易感人群中的一种传染性病原体--结核分枝杆菌引起的。 个体，但我们还不能分类或预测那些易患肺结核病的人的结果 那些容易抵抗的人。在一定程度上，这反映了有关基因类型的知识差距可能会增加 易感性，并在经过验证的疾病中相关(例如，肺蛋白生物标志物的血清)被测量 单独签名或组合签名。我们通过使用不同的近交系(DO)小鼠来解决这些知识差距， 具有丰富遗传多样性和杂合性的种群，就像人类种群一样。而且，像人类一样， 低剂量的结核分枝杆菌感染DO小鼠会产生一系列后果，从高度易感到高度敏感。 具有抵抗力，并有许多中间结果。在本提案中，我们使用DO种群来：1)识别和测试 基因分型(等位基因和有统计学意义的基因座)预测结果的能力 类别(类别)；以及2)识别和测试肺和血清生物标记物(蛋白质)和肉芽肿特征，以 确定诊断类别(类别)；以及3)识别和测试符合以下条件的血清生物标志物(蛋白质)特征 可以在疾病临床表现前的3周内预测疾病的发病。最佳表演奖 签名将使用来自人类的样本进行测试。总的来说，这些研究的结果将产生新的 关于肺结核病相关性的可翻译知识(对诊断有用)，以及基因分型和 血清蛋白信号(对预后有用)。

PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) is caused by an infectious pathogen, Mycobacterium tuberculosis (M.tb) in susceptible individuals, but we cannot yet classify or predict outcomes in those prone to pulmonary TB disease versus those prone to resistance. In part, this reflects knowledge gaps regarding genotypes that may increase susceptibility, and in validated disease correlates (e.g. serum of lung protein biomarkers) measured individually, or combined signatures. We address these knowledge gaps by using Diversity Outbred (DO) mice, a population with abundant genetic diversity and heterozygosity, like the human population. Also, like humans, a low dose M.tb infection of DO mice produces a spectrum of outcomes, from highly susceptible to highly resistant, and many intermediate outcomes. In this proposal, we use the DO population to: 1) Identify and test the capacity of genotypic (alleles and statistically significant loci) to predict outcomes such as diagnostic category (class); and 2) To identify and test lung and serum biomarker (protein) and granuloma signatures to determine diagnostic category (class); and 3) To identify and test serum biomarker (protein) signatures that can forecast disease onset, within a 3-week window before illness manifests clinically. The best performing signatures will be tested using samples from humans. Collectively, results from these studies will generate new translatable knowledge regarding correlates of pulmonary TB (useful for diagnostics), and genotypic and serum protein signatures (useful for prognostics).