Understanding ischemia in children with tuberculous meningitis (iThemba)

了解结核性脑膜炎儿童的缺血情况 (iThemba)

• 批准号: 10674682
• 负责人: James Alexander Seddon
• 金额: $ 44.85万
• 依托单位: STELLENBOSCH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674682
• 关键词: Acute; Address; Affect; Anatomy; Anticoagulants; Area; Artificial Intelligence; Bioinformatics; Biological; Biology; Blood; Blood Vessels; Blood specimen; Brain; Brain Injuries; Cerebral Infarction; Cerebral Ischemia; Cerebrospinal Fluid; Cessation of life; Characteristics; Child; Childhood; Clinical; Clinical Research; Coagulation Process; Computer Simulation; Data; Development; Diagnosis; Disease; Endothelium; Evolution; Functional disorder; Future; Gene Expression; Genes; Goals; Image; Immunoassay; Infarction; Inflammation; Inflammatory; Ischemia; Ischemic Penumbra; Laboratories; Left; Machine Learning; Magnetic Resonance Imaging; Mass Spectrum Analysis; Measures; Meningeal Tuberculosis; Methods; Molecular; Morbidity - disease rate; Neurodevelopmental Deficit; Neurologic; Neurosciences; Outcome; PET/CT scan; Pathogenesis; Pathogenicity; Pathologic Processes; Pathway interactions; Phenotype; Plasma; Population; Probability; Process; Proteins; Proteomics; Public Health; RNA; Radiologic Finding; Radiology Specialty; Research; Research Infrastructure; Sampling; South Africa; Survivors; Techniques; Therapeutic; Therapeutic Intervention; Thrombosis; Time; Tissues; Tuberculosis; Vasculitis; Work; brain dysfunction; cerebral oxygenation; clinical epidemiology; cohort; differential expression; disability; endothelial dysfunction; experience; fluorodeoxyglucose positron emission tomography; follow-up; improved; insight; mortality; multidisciplinary; multiple omics; neglect; neuroimaging; point of care testing; predictive modeling; prospective; protein profiling; radiomics; recruit; response; study population; targeted treatment; thrombotic; transcriptome sequencing; transcriptomics; treatment stratification

PROJECT SUMMARY Background: One million children develop tuberculosis (TB) each year and a quarter of these die. TB meningitis (TBM) is the most severe form of TB disease and even if diagnosed and treated, 20% die and over 50% of survivors are left with permanent neurological disability. Much of the morbidity and mortality associated with TBM is due to infarction caused by large and small vessel inflammation and thrombosis. Despite this, our understanding of the pathogenesis of infarction in TBM is limited, especially in children. We hypothesize that imbalance of the endothelial and plasma pro- and anti-thrombotic mechanisms, inflammatory pathways and vascular proliferative processes underlies cerebral infarction in TBM. Our group has an extensive track record of clinical research into children with TBM and the research team consists of world leaders in the fields of clinical epidemiology, proteomics, transcriptomics, bioinformatics, neurosciences, and radiology. Methods: We will recruit 80 children with probable or confirmed TBM over 30 months and obtain samples of blood and cerebrospinal fluid (CSF). All children will undergo MRI and FDG PET/CT at baseline and at 2 weeks they will have repeat MRI with further blood and CSF samples collected. MRI will then be carried out at 24 weeks will neurodevelopmental assessment at 48 weeks. The neuroimaging will quantify differences between children with and without infarction and relate imaging to clinical presentation and outcome. It will also identify penumbral regions indicating future infarct development/evolution. We will enrich the laboratory analyses with samples from 50 children with probable or confirmed TBM, recruited between 2016 and 2020. RNA sequencing of blood and CSF will be used to identify differentially expressed genes and identify implicated biological pathways between children with and without infarction and between samples taken at baseline and at 2 weeks. Targeted immunoassays and discovery mass spectrometry will be performed on plasma and CSF to determine differences in protein abundance, with a focus on proteins involved in coagulation and endothelial function. Finally, we will integrate the transcriptomics, proteomics and radiomics to generate a comprehensive understanding of the pathogenesis of infarction in children with TBM. We aim to group children into several biological/anatomical phenotypes, each of which may benefit from a different therapeutic approach. We will then explore, using computer simulation, the impact of therapeutic interventions on biological pathways in each phenotype. We anticipate that this work could pave the way for the development of point-of-care tests that could stratify therapy at the time of diagnosis. Impact: A more comprehensive understanding of the pathophysiology of infarction in children with TBM would permit targeted host-directed therapies, with the potential to moderate or eliminate the consequences of this devastating condition.

项目摘要 背景：每年有100万儿童患结核病（TB），其中四分之一死了。结核病脑膜炎 （TBM）是结核病疾病最严重的形式，即使被诊断和治疗，20％死亡，超过50％ 幸存者留下永久性神经疾病。与TBM相关的大部分发病率和死亡率 是由于梗塞由大和小血管炎症和血栓形成引起的。尽管如此，我们的 了解TBM中梗塞发病机理的理解是有限的，尤其是在儿童中。我们假设这一点 内皮和血浆促和抗凝血机制的不平衡，炎症途径和 血管增殖过程是TBM中脑梗塞的基础。我们的小组有广泛的记录 针对TBM儿童和研究小组的临床研究由临床领域的世界领导者组成 流行病学，蛋白质组学，转录组学，生物信息学，神经科学和放射学。 方法：我们将在30个月内招募80名患有可能或确认的TBM的儿童，并获得样本 血液和脑脊液（CSF）。所有儿童将在基线和2周时接受MRI和FDG PET/CT 他们将使用进一步的血液和收集CSF样品进行重复MRI。然后将在24周内进行MRI 48周的神经发育评估。神经影像学将量化儿童之间的差异 有和没有梗塞，并将成像与临床表现和结果相关联。它也将确定半身 指示未来梗塞发展/进化的区域。我们将通过来自 2016年至2020年之间招募的50名患有或确认的TBM的儿童。 CSF将用于鉴定差异表达的基因，并确定在 有和没有梗塞的儿童以及在基线和2周时采集的样本之间。目标 免疫测定和发现质谱将在等离子体和CSF上进行，以确定差异 在蛋白质丰度中，重点是参与凝血和内皮功能的蛋白质。最后，我们会的 整合转录组学，蛋白质组学和放射组学，以对 TBM儿童梗塞发病机理。我们的目标是将儿童分为几个生物学/解剖学 表型，每种表型都可能受益于不同的治疗方法。然后，我们将探索，使用 计算机模拟，治疗干预措施对每种表型中生物途径的影响。我们 预计这项工作可以为开发可能对治疗进行分层的护理测试的发展铺平道路 在诊断时。 影响：对TBM儿童梗塞的病理生理学的更全面理解将 允许有针对性的宿主定向疗法，有可能适度或消除这一后果 毁灭性的条件。