A new combinatorial strategy to selectively manipulate reactive astrocytes in disease

选择性操纵疾病中反应性星形胶质细胞的新组合策略

• 批准号: 9890020
• 负责人: Todd A Fiacco
• 金额: $ 18.48万
• 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: 2019-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890020
• 关键词: Address; Alzheimer' s Disease; Astrocytes; Back; Brain; Brain Diseases; Cells; Cerebral Edema; Chronic; Communities; Data; Development; Diphtheria Toxin; Disease; Disease Progression; Effectiveness; Electroencephalography; Epilepsy; Epileptogenesis; Expression Profiling; Foundations; Gene Expression; Generations; Genetic Recombination; Glial Fibrillary Acidic Protein; Goals; Histologic; Hour; Injury; Ischemia; Kainic Acid; Knock-in Mouse; Knowledge; LCN2 gene; LoxP-flanked allele; Measures; Medical; Mission; Molecular; Monitor; Mosaicism; Mus; Neurodegenerative Disorders; Neuroglia; Neurological Models; Neurons; Outcome; Parkinson Disease; Pathogenesis; Pathway interactions; Process; Public Health; Reporter; Research; Role; Saline; Signal Pathway; Signal Transduction; Stroke; Tamoxifen; Temporal Lobe Epilepsy; Testing; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; Viral; Work; astrogliosis; brain tissue; cell type; combinatorial; effective therapy; experimental study; genetic manipulation; hippocampal sclerosis; improved; insight; male; mind control; mouse model; nervous system disorder; new technology; novel; novel strategies; promoter; virtual

PROJECT SUMMARY Common to virtually all neurodegenerative diseases and brain disorders are changes in a glial cell type called an astrocyte, which become “reactive”. Astrocytes ordinarily provide critical support for neurons and only turn into reactive astrocytes (RAs) following injury or development of disease. A longstanding issue which has remained unknown is whether RAs contribute to, or help alleviate, disease progres- sion. Our long-term goal is to increase understanding of the molecular and cellular underpinnings of diseases and disorders of the nervous system through increased understanding of the role of reactive astrocytes. The objective of this proposal is to deliver a new strategy to selectively alter (eliminate, in- crease, or decrease) the function of only RAs at any point in the progression of nervous system disor- ders. One such disorder for which new treatments are needed is epilepsy. Despite being the third most common neurological disorder in the U.S. after Alzheimer’s disease and stroke, epilepsy is among the least understood of the major chronic medical conditions. Two aims are proposed, with the goal of characterizing this new strategy and providing proof-of-principle for using the approach for the selective manipulation of RAs in disease: In Aim 1, we will first characterize a novel reactive astrocyte inducible Cre transgenic strategy to selectively manipulate RAs in brain disease. In Aim 2, we will then use the new approach to either selectively eliminate RAs or reprogram them back into non-reactive astrocytes at various stages during the development of epilepsy. Our work will provide new knowledge on the pro- tective vs. detrimental roles of reactive astrocytes in the development of epilepsy. The rationale for the proposed research is that new insight into the role of reactive cell types in disease is an important goal for the development of more efficacious treatments. We anticipate that this research will be transforma- tive, as we will introduce to the research community a powerful new strategy to investigate the role of reactive astrocytes in any disease or disorder of the nervous system.

项目概要 几乎所有神经退行性疾病和脑部疾病的共同点是神经胶质细胞类型的变化 称为星形胶质细胞，它变得“反应性”。星形胶质细胞通常为神经元提供关键支持 并且只有在受伤或发生疾病后才会变成反应性星形胶质细胞（RA）。一个长期存在的 仍然未知的问题是 RA 是否有助于或有助于缓解疾病进展。 锡安。我们的长期目标是增进对分子和细胞基础的了解 通过增加对反应性作用的了解来预防神经系统疾病和紊乱 星形胶质细胞。该提案的目标是提供一种新的策略来有选择地改变（消除、消除） 在神经系统紊乱进展的任何时刻，仅 RA 的功能会增加或减少） 德斯。一种需要新疗法的疾病是癫痫。尽管排名第三 继阿尔茨海默病和中风之后，癫痫是美国常见的神经系统疾病之一 对主要慢性病的了解最少。提出了两个目标，其目标是 描述了这一新策略的特征，并为使用该方法进行选择性的验证提供了原理证明 在疾病中操纵 RA：在目标 1 中，我们将首先描述一种新型反应性星形胶质细胞诱导型 Cre 转基因策略选择性操纵 RA 治疗脑疾病。在目标 2 中，我们将使用 选择性消除 RA 或将其重新编程回非反应性星形胶质细胞的新方法 在癫痫发展的不同阶段。我们的工作将提供有关亲的新知识 反应性星形胶质细胞在癫痫发展中的保护作用与有害作用。理由如下： 拟议的研究表明，对反应性细胞类型在疾病中的作用的新见解是一个重要目标 以开发更有效的治疗方法。我们预计这项研究将带来变革 积极的，因为我们将向研究界介绍一个强大的新策略来研究 神经系统任何疾病或紊乱中的反应性星形胶质细胞。