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

基本信息

批准号：
10334891
负责人：
Todd A Fiacco
金额：
$ 6.22万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10334891
关键词：
Acute Astrocytes Award Brain Brain Diseases Brain Injuries Cells Chronic Chronic Phase Communicable Diseases Communities Data Detection Development Disease Disease Progression Doctor of Philosophy Drug abuse Electrophysiology (science)Encephalitis Flow Cytometry Foundations Future Gene Expression Generations Genes Glioma Glutamate Transporter Goals Heterogeneity Immune response Infection Inflammation Inflammatory Knowledge Laboratories Messenger RNA Mission Modeling Molecular National Institute of Drug Abuse Neurodegenerative Disorders Neurologic Neurons Neurosciences Noise Parents Pathology Population Process Production Public Health Reporter Research Research Personnel Role Science Signal Transduction Substance abuse problem System TFRC gene Time Transgenic Organisms Translating United States National Institutes of Health Work career cell type chemokine chronic infection combinatorial cytokine design doctoral student effective therapy electrical property experience experimental study genetic manipulation improved innovation insight methamphetamine exposure methamphetamine use nervous system disorder neuroinflammation novel novel strategies parent grant prevent programs tool translatome virtual

项目摘要

SUMMARY (from R01DA048815). While numerous transgenic tools and approaches exist for manipulation of gene expression in many cell types found in a healthy brain, tools designed to target and study cells present only in the diseased or damaged brain are lacking. Common to virtually all neurodegenerative diseases, brain injuries and infections are neuroinflammatory and immune responses characterized by changes in astrocytes. These cells ordinarily provide critical support for neurons, but become reactive astrocytes (RAs) in brain disease and inflammation. A longstanding and still unresolved issue is whether RAs contribute to or help alleviate disease progression. The objective of this application is to deliver to the neuroscience community a new combinatorial transgenic strategy and toolkit to specifically target RAs in disease. This toolkit will enable researchers to selectively alter (i.e., eliminate, increase, or decrease) gene expression only in RAs at any point in the progression of brain disease and inflammation. Astrocyte populations from acute and chronic methamphetamine use will be analyzed. Three aims are proposed: In Aim 1, we will characterize the Cre transgenic strategy to selectively manipulate gene expression only in RAs in diseased brains. In Aim 2, we will use the new approach to selectively ablate, prevent, or reprogram RAs into non-RAs at various stages of the acute and chronic inflammatory processes. Our work will provide new information on the role of RAs in the early vs. sustained stages of brain inflammation. In Aim 3, we will perform “translatome” analysis to identify the genes uniquely altered in reactive astrocytes during brain inflammation for the first time, providing novel targets for future study. Our innovative approach will allow detection of both inductions and reductions in gene expression with unprecedented signal-to-noise over existing approaches. The rationale for the proposed research is that improving understanding of the cellular and molecular mechanisms of brain disease will provide novel insights for 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.

摘要（来自R01DA048815）。在健康大脑中基础的许多细胞类型中的基因表达，旨在靶向和研究细胞的工具在患病或受损的大脑中，所有神经退行性疾病都没有感染是神经炎症和免疫反应，其特征是星形胶质细胞的变化。细胞通常提供批判性支撑fornuron，但在脑部疾病和炎症。进展。转基因策略和工具包专门针对疾病的RA。选择性更改（即消除，增加或减少）基因表达在RAS中的任何一点脑疾病和炎症的进展。急性和慢性甲基苯丙胺使用的星形细胞种群将提出三个目标：在AIM 1中，我们将表征仅在RAS中选择基因表达的CRE转基因策略在AIM 2中，我们将使用Newe方法进行选择性灌溉或重新编程在急性和慢性炎症过程的各个阶段的非RAS。 RA在泪液中的作用与脑部炎症的稳定阶段的信息。 “翻译”分析以识别脑炎症期间反应性星形胶质细胞中唯一的基因第一次为未来的研究提供新的目标。诱导和降低基因表达，未经预言的信号对鼻子拟议研究的理由是改善细胞和分子机制大脑疾病将为我们提供更多有效治疗的见解这项研究具有变革性，因为我们将向研究社区介绍一种强大的新战略研究反应性细胞类型在神经系统的任何疾病中的作用。