Biology and Biosignatures of Anti-Tuberculosis Treatment Response

 描述(申请人提供)：结核病(TB)是一种由结核分枝杆菌引起的细菌性疾病，对公众健康有重大影响，但治疗困难且旷日持久。因此，大力致力于开发新的抗结核药物和治疗方案。获得新的抗结核药物的一个主要障碍是进行临床试验的困难和成本。南非不仅是一个结核病流行地区，而且也是一个已经成为临床研究和临床试验重点的国家。我们基于结核病治疗不同阶段和结果的外周血液转录组、蛋白质组、代谢组和宿主细胞免疫反应的强有力的初步证据，包括多杆菌和少杆菌状态，支持了创新的假设，即在结核病治疗过程中免疫和代谢反应发生了重新编程。这种重新编程在结核病患者中根据他们对治疗的反应而有所不同，因此可以识别快速反应与缓慢反应、治疗失败和复发的区分生物标志物。拟议的ICIDR项目建立了一个由南非和美国科学家组成的联盟，该联盟在临床和基础研究方面具有专业知识，以解决生物标记物和生物签名的开发问题，以更好地监测和预测临床试验期间的治疗结果。这项工作将利用现有的临床样本和从南非正在进行的临床研究中收集的样本进行。它将整合南非和美国应用的各种基于“OMIC”的分析平台的数据，以识别代表结核病治疗过程中遇到的少杆菌状态的扰动生物路径。此外，我们将链接到由惠康信托基金资助的现有南非治疗后疫苗临床试验“结核病治疗性疫苗的临床开发”，以允许预期收集可用于测试和验证治疗反应的生物标记物和签名的样本。因此，该项目建议开发新的工具，这些工具可以应用于南非的一个重大公共卫生问题，并将提高该国和其他地方抗结核新药的临床试验的绩效。此外，拟议的研究为南非科学家提供了非同寻常的培训机会，将最先进的基础科学与以结果为导向的临床研究计划相结合。

 DESCRIPTION (provided by applicant): Tuberculosis (TB) is a bacterial disease caused by Mycobacterium tuberculosis and that has a major public health impact, but for which treatment is difficult and protracted. Thus, significant efforts are devoted to the development of new anti-TB drugs and treatment regimens. A major impediment in obtaining new anti-TB drugs is the difficulty and cost in performing clinical trials. South Africa is not only a region endemic for TB but is also a country that has become a focus of clinical research and clinical trials. Our strong preliminary evidence based on peripheral blood transcriptome, proteome, metabolome and host cellular immune responses during different stages and outcomes of TB treatment, including multi- and paucibacillary states provide support for the innovative hypothesis that reprogramming of the immune and metabolic responses occurs during TB treatment. This reprogramming differs among TB patients based on their response to treatment, and thus allows for the identification of distinguishing biomarkers for rapid vs. slow response, failed treatment and relapse. The proposed ICIDR project establishes a consortium of South African and US scientists with expertise in clinical and basic research to address the development of biomarkers and biosignatures to better monitor and predict treatment outcome during clinical trials. This work will be performed with existing clinical samples and those being collected form ongoing clinical studies in South Africa. It will integrate data from various "omic" based analytical platforms being applied in South Africa and the US to identify perturbed biological pathways representative of the paucibacillary states encountered during TB treatment. Additionally, we will link to an existing South African post-treatment vaccine clinical trail "Clinical Development of a Therapeutic Vaccine for Tuberculosis" funded through the Wellcome Trust to allow prospective collection of samples that can be used to test and validate biomarkers and signatures of treatment response. Thus, this project proposes to develop new tools that can be applied to a significant public health problem in South Africa and that will enhance the performance of clinical trials of new anti-TB drugs in this country and elsewhere. Moreover, the proposed research provides extraordinary training opportunities for South African scientists to integrate state-of-the-art basic science with outcome driven clinical research programs.