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 结核病是一种全球性疾病，影响着世界上主要是发展中地区的数百万人。中央 神经系统结核病（CNS-TB）是最严重的肺外形式的疾病，尽管 积极的治疗干预，可以有高达80%的死亡率。理解的重大障碍 疾病的发病机制存在，这转化为不良的诊断和治疗结果。因此，提高洞察力 CNS TB中神经胶质细胞免疫细胞的相互作用，以及调节大脑病理学的因素需要一个全面的 分子和细胞的观点。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，以开发新的，有效的， 广泛使用的治疗方法。单细胞/核RNA测序（sc/snRNA-seq）基因表达 分析允许对神经发病机制中涉及的细胞和分子通路进行大规模观察， 确定结核病状态之间新的差异的潜力。在这项研究中，我们将调查 M.脑结核感染的临床和实验研究 条件，以确定CNS-TB如何开始和进展到不同的结果。这是通过以下方式实现的： 在我们最近完成的全球大脑R21期间生成的初步snRNA-seq数据。我们假设 分枝结核病侵入中枢神经系统是由于未能产生适当的神经免疫反应， CNS驻留和外周募集的免疫细胞。这得到了我们的初步数据的有力支持， 人类和啮齿动物snRNA-seq研究。通过探索正常和非正常细胞中的转录差异， 疾病状态，我们将能够识别细胞类型特异性的分子和细胞过程， CNS-TB的发病机制，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CNS和免疫信号传导将使我们能够开发新的疗法， 改善临床结果。为了验证我们的中心假设，我们将确定跨膜的分子途径。 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 CNS-TB的信号传导框架。除了我们的科学目标，我们还将扩大 单细胞基因表达分析平台，建立在开普敦大学（UCT）在我们的研究期间， 全球大脑R21为更广泛的非洲科学界提供支持。我们的目标是提供项目培训 规划、库准备和数据分析。当完成后，我们将有一个新的理解 细胞类型特异性炎症信号传导事件，驱动CNS-TB，并将准备参与新的 分子靶点，以改善CNS-TB的结果。此外，UCT将成为一个单一的 细胞生物学，启动下一代非洲科学家的科学事业， 全非洲的医疗保健。