Using Single Cell Biological Approaches to Understand CNS TB

使用单细胞生物学方法了解中枢神经系统结核

• 批准号: 10739081
• 负责人: Chris G Dulla
• 金额: $ 48.41万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739081
• 关键词: 2019-nCoV; Affect; Africa; African; Biochemistry; Biological; Brain; Brain Diseases; Brain Pathology; C3HeB/FeJ Mouse; Cell Communication; Cell Death; Cell Nucleus; Cell physiology; Cells; Cellular biology; Central Nervous System Tuberculosis; Cessation of life; Clinical; Communities; Computational Biology; Data; Data Analyses; Development; Diagnosis; Disease; Education; Event; Fatality rate; Future Generations; Gene Expression Profile; Gene Expression Profiling; Generations; Genetic Transcription; Goals; Granulomatous; Growth; Healthcare; Human; Human Pathology; Immune; Immune signaling; Immune system; Immunocompromised Host; Immunohistochemistry; Infection; Inflammatory; Infrastructure; Invaded; Libraries; Meningeal Tuberculosis; Meningitis; Molecular; Molecular Target; Mouse Strains; Mus; Mycobacterium tuberculosis; Neuroimmune; Neurologic; Neurologic Dysfunctions; Neuropathogenesis; Outcome; Pathogenesis; Pathway interactions; Patients; Peripheral; Persons; Phenotype; Preparation; Program Development; Reagent; Research; Research Infrastructure; Resected; Rodent; Rodent Model; Sampling; Scientist; Severities; Signal Transduction; South Africa; Specificity; Structure; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Training; Translating; Treatment outcome; Tuberculoma; Tuberculosis; Universities; Work; brain tissue; career; cell type; clinical phenotype; differential expression; human RNA sequencing; human data; human disease; improved; innovation; insight; mouse model; neuroinflammation; next generation; novel; novel therapeutics; pathogen; recruit; response; single nucleus RNA-sequencing; single-cell RNA sequencing; skill acquisition; skills; synergism; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Tuberculosis is a global disease affecting millions of people in primarily developing regions of the world. Central nervous system tuberculosis (CNS-TB) is the most severe extra pulmonary form of the disease, which, despite aggressive therapeutic intervention, can have a fatality rate of up to 80%. Significant barriers to understanding disease pathogenesis exist, which translates to poor diagnosis and treatment outcomes. Thus, improved insight into neuro-glial-immune cell interactions in CNS TB, and the factors that regulate brain pathology require a global molecular and cellular perspective. Our long-term goal is to understand the mechanisms associated with the development of CNS-TB, and different CNS-TB outcomes, in order to develop novel, effective, and broadly accessible therapeutics. Single cell/nucleus RNA sequencing (sc/snRNA-seq) gene expression analysis allows for a large-scale view of the cells and molecular pathways involved in neuropathogenesis, with the potential to identify novel differences between TB diseased states. In this study, we will investigate transcriptional changes induced by M. tuberculosis infection of the brain under clinical and experimental conditions to determine how CNS-TB starts and progresses to different outcomes. This is made possible by preliminary snRNA-seq data generated during our Global Brain R21 that we recently completed. We hypothesize that M. tuberculosis invades the CNS due to the failed generation of an appropriate neuroimmune response in CNS resident and peripherally recruited immune cells. This is strongly supported by our preliminary data from human and rodent snRNA-seq studies. By exploring the transcriptional differences in cells from normal and diseased states we will be able to identify the cell type-specific molecular and cellular processes that underpin the pathogenesis of CNS-TB, including neuroinflammation and immune system engagement. Understanding cell type-specific CNS and immune signaling in CNS-TB will enable us to develop novel therapies and improve clinical outcomes. To test our central hypothesis, we will determine the molecular pathways across CNS and immune cells that define clinical phenotypes in patients with CNS-TB and create a full disease spectrum signaling framework of CNS-TB using multiple mouse models. In addition to our scientific aims, we will expand the single cell gene expression analysis platform, established at the University of Cape Town (UCT) during our Global Brain R21 support, to the broader African scientific community. We aim to provide training in project planning, library preparation, and data analysis. When complete, we will have a novel understanding of the cell type-specific inflammatory signaling events that drive CNS-TB and will be poised to engage novel molecular targets to improve CNS-TB outcomes. Furthermore, UCT will be established as a hub of single cell biology, to launch scientific careers of the next generation of African scientists, and to improve health care across Africa.

项目摘要 结核病是一种全球疾病，影响了世界主要发展地区的数百万人。中央 神经系统结核病（CNS-TB）是该疾病中最严重的肺部形式，尽管 积极的治疗干预措施的死亡率高达80％。理解的重大障碍 存在疾病发病机理，这转化为诊断和治疗结果不良。因此，改善了见识 进入中枢神经系统结核病的神经胶质免疫细胞相互作用，调节脑病理的因素需要全球 分子和细胞透视。我们的长期目标是了解与 CNS-TB的发展以及不同的CNS-TB结果，以发展新颖，有效和 广泛可访问的治疗学。单细胞/核RNA测序（SC/SNRNA-SEQ）基因表达 分析允许对参与神经病发生的细胞和分子途径进行大规模视野，并具有 识别结核病患病状态之间新差异的潜力。在这项研究中，我们将调查 在临床和实验性下，大脑的结核分枝杆菌感染引起的转录变化 确定CNS-TB如何启动并发展到不同结果的条件。这是由 我们最近完成的全球大脑R21中生成的初步SNRNA-SEQ数据。我们假设 结核分枝杆菌因在适当的神经免疫反应失败而侵入CNS 中枢神经系统驻留和周围招募的免疫细胞。我们的初步数据从 人和啮齿动物SnRNA-Seq研究。通过探索正常和 患病状态我们将能够鉴定基于基础的细胞类型特异性分子和细胞过程 CNS-TB的发病机理，包括神经炎症和免疫系统参与。理解 CNS-TB中的细胞类型特异性中枢神经系统和免疫信号传导将使我们能够开发新的疗法和 改善临床结果。为了检验我们的中心假设，我们将确定跨越的分子途径 CNS和免疫细胞定义CNS-TB患者的临床表型并创建完整的疾病谱 使用多个鼠标模型的CNS-TB信号传导框架。除了我们的科学目标，我们还将扩展 单细胞基因表达分析平台，在我们的开普敦大学（UCT）建立 全球大脑R21支持，对更广泛的非洲科学界。我们旨在提供项目培训 计划，图书馆准备和数据分析。完成后，我们将对 驱动CNS-TB的细胞类型特异性炎症信号传导事件，并将有望参与新颖 改善CNS-TB结果的分子靶标。此外，UCT将被确定为单个枢纽 细胞生物学，启动下一代非洲科学家的科学职业，并改善 整个非洲的医疗保健。