Human Brain Organoid: a new CNSTB model

人脑类器官：一种新的 CNSTB 模型

• 批准号: 10453987
• 负责人: Matyas Sandor
• 金额: $ 64.91万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-19 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453987
• 关键词: Affect; Animal Model; Antibiotics; Bacteria; Biological Models; Brain; Cell Differentiation process; Cells; Central Nervous System Infections; Central Nervous System Tuberculosis; Dangerousness; Development; Differentiation and Growth; Disease; Educational workshop; Effectiveness; Functional disorder; Gene Expression; Human; Immune response; Immunity; In Vitro; Infection; Inflammatory; Knowledge; Lead; Left; Meningeal Tuberculosis; Microglia; Modeling; Molecular; Mus; Mycobacterium Infections; Mycobacterium tuberculosis; Nervous System Trauma; Neuraxis; Neurons; Organoids; Outcome; Pathogenesis; Pathology; Phagocytes; Pharmaceutical Preparations; Physiology; Pluripotent Stem Cells; Public Health; Research; Risk; Site; Testing; Tissues; Tuberculosis; United States National Institutes of Health; Work; brain cell; brain parenchyma; cell type; disability; human disease; human model; insight; meetings; monocyte; mortality risk; mouse model; mycobacterial; nerve stem cell; neuronal replacement; novel; novel therapeutics; precursor cell; progenitor; recruit; relating to nervous system; response; stem cells; therapy development; tuberculosis treatment; uptake

PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) of the central nervous system (CNS) is the most dangerous form of M. tuberculosis (Mtb) infection. For these cases, the risk of mortality is extremely high; those who survive are left with an elevated risk of severe neurological damage and disability. Despite its public health importance, current understanding of the dissemination of Mtb in the brain and anti-mycobacterial immunity within the human brain parenchyma is limited. This represents a roadblock for developing a better cure for TB meningitis. This concern motivated the NIH to organize a TB Meningitis workshop to develop a roadmap for advancing CNS TB research. The workshop established that creating human in vitro platforms would facilitate research on the field and significantly contribute to the understanding of cellular and molecular insights into the pathogenesis of CNS TB. This proposal will test and optimize a new platform, Mtb infection of human brain organoids, to study CNS Mtb infection. Previously, we have found that mycobacterial infection of the murine brain leads to protective immune responses and bacterial control. While useful, murine model systems do not always reflect the many aspects of human disease, and the application of human single and multi-component neuronal tissues would be more appropriate. Mtb infects phagocytes, and most of the Mtb in the brain after CNS infection is located in recruited monocytes and local microglia. We discovered that neural progenitors could also be infected with Mtb. Under this proposal's aegis, we will test how the different infected phagocytes contribute to brain tuberculosis. The two main objectives of this proposal are to understand the mechanism and consequences of bacterial uptake by neural progenitors (Aim 1) and to apply neuronal organoids to test mechanisms of Mtb dissemination and brain cell responses to Mtb infection. We propose to compare the effects of different Mtb-infected phagocytes on human neural tissue (Aims 2 and 3). Successful completion of this work will lead to new knowledge on a novel aspect of brain TB concerning neural progenitors' infection. It raises the possibility that Mtb effects neuronal replacement at sites where neurons are constitutively generated. In addition, we develop new human model platforms to study the dissemination of Mtb into the brain and brain-specific responses to Mtb infection.

项目摘要/摘要 中枢神经系统（CNS）的结核病（TB）是结核分枝杆菌（MTB）的最危险形式 感染。对于这些情况，死亡率的风险极高。那些生存的人的风险较高 严重的神经损害和残疾。尽管公共健康的重要性，但当前对 大脑中MTB的传播和人脑实质内的抗细菌免疫受到限制。 这代表了开发更好治愈结核炎脑膜炎的障碍。这种关注激发了NIH 组织一个结核病脑膜炎研讨会，以开发用于推进CNS结核病研究的路线图。车间 确定建立人类的体外平台将有助于该领域的研究，并显着贡献 理解细胞和分子洞察中心结核病的发病机理。该建议将测试 并优化一个新的平台，即人脑器官的MTB感染，以研究CNS MTB感染。 以前，我们发现鼠大脑的分枝杆菌感染会导致保护性免疫反应 和细菌控制。尽管有用，但鼠模型系统并不总是反映人类的许多方面 疾病，人类单一和多组分神经组织的应用将更合适。 MTB感染吞噬细胞，以及CNS感染后大脑中的大多数MTB位于招募的单核细胞中 和局部小胶质细胞。我们发现神经祖细胞也可以被MTB感染。根据该提议的 宙斯盾，我们将测试不同感染的吞噬细胞如何促进脑结核病。 该提案的两个主要目标是了解细菌的机制和后果 神经祖细胞的摄取（AIM 1）并应用神经元器官来测试MTB传播机制 和脑细胞对MTB感染的反应。我们建议比较不同MTB感染的吞噬细胞的影响 在人类神经组织上（目标2和3）。 成功完成这项工作将导致有关大脑结核病新颖方面的新知识 神经祖细胞感染。它增加了MTB在站点效应神经元置换的可能性 神经元是组成型产生的地方。此外，我们开发了新的人类模型平台 研究MTB向大脑的传播，并对MTB感染的大脑特异性反应。

项目成果

Modeling Infectious Diseases of the Central Nervous System with Human Brain Organoids.

• DOI: 10.1016/j.trsl.2022.06.013
• 发表时间: 2022-07
• 期刊: Translational research : the journal of laboratory and clinical medicine
• 作者: Thanthrige Thiunuwan Priyathilaka;C. Laaker;Melinda Herbath;Z. Fabry;M. Sandor