ULTIMATE

最终的

• 批准号: 10058722
• 负责人: Guy Thwaites
• 金额: $ 91.53万
• 依托单位: STICHTING RADBOUD UNIVERSITEIT
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058722
• 关键词: ULTIMATE

Project Summary/abstract Tuberculous meningitis (TBM) has a very high mortality, especially in HIV-infected patients, and there is an urgent need to improve treatment. Intracerebral inflammation has long been recognized as an important determinant of TBM outcome and adjunctive anti-inflammatory corticosteroid treatment have been shown to prevent death, but not disability, in HIV-uninfected people with TBM. Corticosteroids represent the only host directed therapy of proven benefit in tuberculosis treatment, yet their effect is modest, their adverse effects substantial, and the mechanism by which they reduce mortality is unknown. Furthermore, there is evidence for heterogeneity in their effect, dependent upon inter-individual variation in the intracerebral inflammatory response; and whether those with HIV-infection benefit from corticosteroids remains uncertain. Cellular metabolism is critical for the function of immune cells. We recently found that high concentrations of cerebrospinal fluid (CSF) tryptophan strongly predicted mortality in Indonesian TBM patients. Using genome- wide SNP analysis we identified 11 quantitative trait loci that were associated with both CSF tryptophan concentrations and survival in a separate patient cohort. Many questions remain. How is tryptophan metabolism altered during TBM? How does it correlate with inflammation, immunopathology, and response to corticosteroids? How is tryptophan metabolism genetically regulated? Lastly, and very importantly, what is the effect of HIV co-infection on tryptophan metabolism before and during TBM treatment? Our aim is to address these questions by integrating data and specimens from large studies in Vietnam and Indonesia with state-of-the-art omics technology and systems biology in the Netherlands and USA. Based on our previous study findings ULTIMATE’s first aim is to define tryptophan metabolism in 1500 TBM patients and 300 controls with other brain infections from previous studies in Indonesia and Vietnam, using state-of-the-art LC-MS platforms. Our second aim is to define the genetic regulation of tryptophan metabolism in TBM with a combination of genome-wide SNP-typing of DNA from the same patient group and whole genome sequencing of a subset (n=200). Our third aim is to identify biomarkers predicting the effect of corticosteroids, and discover potential new targets for host-directed therapy by integrating clinical and neuroradiological data with CSF transcriptomics, metabolomics, and host genotyping of 600 patients randomized to corticosteroids or placebo. We will address these 3 aims in HIV-infected and uninfected patients because HIV-associated TBM has higher mortality and different immunopathology. Our strong preliminary data, unique access to two large bioarchives and on-going randomized controlled trials in TBM, and expertise in integration of large-scale clinical and multi-layer ‘omics’ data promises to provide a step-change in understanding TBM pathogenesis and discovery of new targets for future host-directed therapies.

项目概要/摘要 脑膜炎（TBM）的死亡率非常高，尤其是在HIV感染患者中， 迫切需要改善治疗。脑内炎症长期以来被认为是一种重要的 TBM预后的决定因素和持续的抗炎皮质类固醇治疗已被证明， 预防未感染艾滋病毒的结核分枝杆菌感染者死亡，但不致残。皮质类固醇代表了唯一的宿主 在结核病治疗中，已证明有益的定向疗法，但其效果是温和的，其不良反应 但是，这些药物的疗效是显著的，它们降低死亡率的机制尚不清楚。此外，有证据表明， 其作用的异质性取决于脑内炎性细胞因子的个体间差异， HIV感染者是否能从皮质类固醇中获益仍不确定。 细胞代谢对免疫细胞的功能至关重要。我们最近发现高浓度的 脑脊液（CSF）色氨酸强烈预测印尼TBM患者的死亡率。利用基因组- 通过广泛的SNP分析，我们确定了11个数量性状基因座，这些基因座与CSF色氨酸 浓度和存活率在一个单独的患者队列。许多问题仍然存在。色氨酸怎么样 在TBM过程中改变了新陈代谢？它如何与炎症、免疫病理学和对 皮质类固醇？色氨酸代谢是如何遗传调节的？最后，也是非常重要的一点， TBM治疗前和治疗期间HIV合并感染对色氨酸代谢的影响？ 我们的目标是通过整合来自越南大型研究的数据和标本来解决这些问题， 印度尼西亚，在荷兰和美国拥有最先进的组学技术和系统生物学。基于 我们先前的研究发现，ULTIMATE的第一个目标是确定1500例TBM患者的色氨酸代谢， 300名患有其他脑部感染的对照，来自印度尼西亚和越南先前的研究，使用最先进的 LC-MS平台。我们的第二个目标是用一种新的方法来确定TBM中色氨酸代谢的遗传调控。 来自同一患者组的DNA的全基因组SNP分型和全基因组测序的组合 （n=200）。我们的第三个目标是确定预测皮质类固醇作用的生物标志物，并发现 通过整合临床和神经放射学数据与CSF，为宿主导向治疗提供潜在的新靶点 转录组学、代谢组学和宿主基因分型，随机分配至皮质类固醇或安慰剂组的600名患者。 我们将在HIV感染和未感染的患者中解决这3个目标，因为HIV相关的TBM具有更高的 死亡率和不同的免疫病理学。 我们强大的初步数据，独特的访问两个大型生物档案和正在进行的随机对照试验 大规模临床和多层“组学”数据整合方面的专业知识有望提供 了解TBM发病机制和发现未来宿主导向的新靶点的步骤变化 治疗