Exploring the role of reactive astrocytes in brain inflammation using a novel combinatorial strategy

使用新型组合策略探索反应性星形胶质细胞在脑炎症中的作用

• 批准号: 9980839
• 负责人: Todd A Fiacco
• 金额: $ 42.54万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980839
• 关键词: Acute; Address; Alzheimer' s Disease; Astrocytes; Back; Brain; Brain Diseases; Brain Injuries; Cell physiology; Cells; Chronic; Communities; Complement; Data; Detection; Development; Disease; Disease Progression; Effectiveness; Encephalitis; Epilepsy; Expression Profiling; Foundations; Future; Gene Expression; Generations; Genes; Genetic Recombination; Glial Fibrillary Acidic Protein; Histologic; Immune response; Infection; Inflammation; Inflammatory; Injury; Intraventricular Injections; Ischemia; Knock-in Mouse; Knowledge; LCN2 gene; LoxP-flanked allele; Measures; Messenger RNA; Mission; Modeling; Molecular; Mosaicism; Mus; Neurodegenerative Disorders; Neuroglia; Neurons; Noise; Outcome; Parasites; Parasitic infection; Parkinson Disease; Pathway interactions; Peripheral; Process; Public Health; Reporter; Research; Research Personnel; RiboTag; Role; STAT3 gene; Signal Pathway; Signal Transduction; Tamoxifen; Testing; Time; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Transgenic Mice; Transgenic Organisms; Translating; Tumor stage; United States National Institutes of Health; Viral; Work; astrogliosis; base; brain tissue; cell type; combinatorial; design; effective therapy; experimental study; genetic approach; genetic manipulation; improved; inhibitor/antagonist; innovation; insight; mind control; nervous system disorder; neuroinflammation; novel; novel strategies; prevent; promoter; stem; tool; translatome; virtual; virus genetics

PROJECT SUMMARY While numerous transgenic tools and approaches exist to enable manipulation of gene expression in many cell types in the healthy brain, tools designed to target and study cells present only in the dis- eased or damaged brain are lacking. Common to virtually all neurodegenerative diseases, brain injuries and infections is a neuroinflammatory and immune response characterized by changes in astrocytes, which become “reactive”. Astrocytes ordinarily provide critical support for neurons and only turn into reactive astrocytes (RAs) in brain disease and inflammation. A longstanding issue which has remained unknown is whether RAs contribute to or help alleviate disease progression. The objective of this appli- cation is to deliver a new combinatorial transgenic strategy and toolkit to specifically target RAs in dis- ease. This toolkit will enable researchers to selectively alter (eliminate, increase, or decrease) gene ex- pression only in RAs at any point in the progression of brain disease and inflammation. Brain infection by the parasite Toxoplasma gondii will serve as a model of brain inflammation stemming from infection. Three aims are proposed: In Aim 1, we will first characterize the Cre transgenic strategy to selectively manipulate gene expression only in RAs in brain disease. In Aim 2, we will then use the new approach to selectively ablate, prevent, or reprogram RAs back into non-reactive astrocytes at various stages during the acute and chronic inflammatory process. Our work will provide new information on the role of reactive astrocytes in the early vs. sustained stages of brain inflammation. In Aim 3, we will perform “translatome” analysis to identify genes uniquely altered in reactive astrocytes during brain inflamma- tion for the first time, providing novel targets for future study. Our innovative approach will allow detec- tion of both inductions and reductions in gene expression with unprecedented signal-to-noise over ex- isting approaches. The rationale for the proposed research is that improving understanding of the cellu- lar and molecular mechanisms of brain disease will provide novel insights into the development of more effective treatments. We anticipate that this research will be transformative, as we will introduce to the research community a powerful new strategy to investigate the role of reactive cell types in any disease or disorder of the nervous system.

项目摘要 尽管存在许多转基因工具和方法，以使基因表达在 健康大脑中的许多细胞类型，旨在靶向和研究细胞的工具仅存在于疾病中 缺乏容易或受损的大脑。几乎所有神经退行性疾病，脑损伤常见 感染是一种神经炎症性和免疫激素，其特征是星形胶质细胞的变化， 它变为“反应性”。星形胶质细胞通常为神经元提供关键的支持，只变成 脑疾病和炎症中的反应性星形胶质细胞（RAS）。一个长期存在的问题仍然存在 未知是RAS是否有助于减轻疾病进展。该应用的目的 阳离子是为了提供一种新的组合转基因策略和工具包，以专门针对RAS 舒适。该工具包将使研究人员能够选择性地改变（消除，增加或减少）基因 仅在脑部疾病和感染进展的任何时刻在RAS中陈述。脑感染 通过寄生虫弓形虫，弓形虫将作为感染引起的脑感染模型。 提出了三个目标：在AIM 1中，我们将首先描述CRE转基因策略以选择性地 仅在RAS中操纵基因表达。在AIM 2中，我们将使用新方法 有选择地灌溉，预防或重新编程RAS在各个阶段中回到非反应性星形胶质细胞中 在急性和慢性炎症过程中。我们的工作将提供有关角色的新信息 早期与脑感染的持续阶段的反应性星形胶质细胞。在AIM 3中，我们将表演 “翻译组”分析以识别脑炎症过程中反应性星形胶质细胞中唯一改变的基因 第一次，为未来的研究提供了新颖的目标。我们的创新方法将允许检测 - 诱导和基因表达的降低以及前所未有的信号 - 噪声 iSting方法。拟议的研究的理由是，提高对Cellu-的理解 大脑疾病的LAR和分子机制将为更多的发展提供新的见解 有效的治疗方法。我们预计这项研究将具有变革性，因为我们将介绍 研究社区一种强大的新策略，以研究反应性细胞类型在任何疾病中的作用 或神经系统的混乱。