Understanding ischemia in children with tuberculous meningitis (iThemba)

了解结核性脑膜炎儿童的缺血情况 (iThemba)

基本信息

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
项目类别：
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

项目摘要

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.

项目概要背景：每年有一百万儿童患上结核病 (TB)，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，仍有 20% 的人死亡，超过 50% 的人死亡幸存者会留下永久性的神经残疾。大部分发病率和死亡率与 TBM 相关是由于大小血管炎症和血栓形成而引起的梗塞。尽管如此，我们的对 TBM 梗死发病机制的了解有限，尤其是儿童。我们假设内皮和血浆促血栓形成机制、抗血栓形成机制、炎症途径和 TBM 中的血管增殖过程是脑梗塞的基础。我们的团队拥有丰富的业绩记录儿童 TBM 临床研究的领导者，研究团队由临床领域的世界领先者组成流行病学、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 名可能或确诊患有 TBM 超过 30 个月的儿童，并获取样本血液和脑脊液（CSF）。所有儿童将在基线和两周时接受 MRI 和 FDG PET/CT 他们将进行重复 MRI 检查，并收集更多血液和脑脊液样本。 MRI 将在 24 周时进行将在 48 周时进行神经发育评估。神经影像学将量化儿童之间的差异有或没有梗塞，并将影像学与临床表现和结果联系起来。它还将识别半影指示未来梗塞发展/演变的区域。我们将用来自的样品丰富实验室分析 2016 年至 2020 年间招募了 50 名可能患有或确诊患有 TBM 的儿童。 CSF将用于识别差异表达基因并识别之间相关的生物途径有和没有梗塞的儿童以及在基线和两周时采集的样本之间的差异。有针对性将对血浆和脑脊液进行免疫测定和发现质谱分析以确定差异蛋白质丰度，重点关注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 TBM 儿童梗塞的发病机制。我们的目标是将儿童分为几个生物学/解剖学组表型，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，治疗干预对每种表型的生物途径的影响。我们预计这项工作可以为开发可以分层治疗的即时测试铺平道路在诊断时。影响：更全面地了解 TBM 儿童梗塞的病理生理学将有助于允许有针对性的宿主定向治疗，有可能减轻或消除这种后果毁灭性的状况。