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: 10343893
• 负责人: James Alexander Seddon
• 金额: $ 46.35万
• 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/10343893
• 关键词: Acute; Address; Affect; Anatomy; Area; Artificial Intelligence; Bioinformatics; Biological; Biology; Blood; Blood specimen; Brain; Brain Injuries; Cerebral Infarction; Cerebrospinal Fluid; Cerebrum; Cessation of life; Characteristics; Child; Childhood; Clinical; Clinical Research; Coagulants; 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; 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; Vascular Proliferation; 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

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，其中四分之一死亡。结核性脑膜炎 (TBM)是最严重的结核病形式，即使得到诊断和治疗， 幸存者会留下永久性的神经残疾。大部分与TBM相关的发病率和死亡率 是由于大、小血管炎症和血栓形成引起的梗塞。尽管如此，我们 对TBM中梗死的发病机制的理解是有限的，特别是在儿童中。我们假设 内皮和血浆促血栓形成和抗血栓形成机制、炎症途径和 血管增生过程是脑梗死的基础。我们的团队有着广泛的记录 该研究团队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：我们将招募80名30个月以上可能或确诊为TBM的儿童， 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检查 他们将再次接受MRI检查，并采集更多血液和CSF样本。然后在24周时进行MRI检查 在48周时进行神经发育评估。神经成像将量化儿童之间的差异 并将影像学与临床表现和结果相关联。它还将识别半影 指示未来梗塞发展/演变的区域。我们将用来自以下地区的样本丰富实验室分析 2016年至2020年间招募了50名可能或确诊患有TBM的儿童。血液RNA测序和 CSF将用于鉴定差异表达的基因，并鉴定与基因表达相关的生物学途径。 有和没有梗死的儿童以及基线和2周时采集的样本之间的差异。针对性 将对血浆和CSF进行免疫测定和发现质谱分析，以确定差异 在蛋白质丰度方面，重点是参与凝血和内皮功能的蛋白质。最后我们将 整合转录组学，蛋白质组学和放射组学，以全面了解 脑梗死的发病机制。我们的目标是将儿童分为几个生物/解剖学 表型，其中每一个可以受益于不同的治疗方法。然后我们将探索，使用 计算机模拟，治疗干预对每个表型中生物途径的影响。我们 我预计这项工作可以为发展可以分层治疗的即时检测铺平道路 在诊断的时候。 影响：更全面地了解TBM儿童梗死的病理生理学， 允许有针对性的宿主导向疗法，有可能减轻或消除这种后果， 具有破坏性的病症