A new combinatorial strategy to selectively manipulate reactive astrocytes in disease

项目摘要 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 并且只有在受伤或疾病发展后才会变成反应性星形胶质细胞（RA）。不上常委的长期 仍然未知问题是RA是否促进或帮助减轻疾病进展- 锡永。我们的长期目标是增加对细胞和分子基础的理解， 神经系统疾病和紊乱，通过增加对反应性 星形胶质细胞该提案的目的是提供一个新的战略，有选择地改变（消除，在- 在神经系统疾病进展过程中的任何一点上，仅增加或减少）RA的功能， ders。需要新治疗的一种疾病是癫痫。尽管是第三大 在美国，癫痫是继阿尔茨海默病和中风之后的一种常见的神经系统疾病。 最不了解的主要慢性疾病。提出了两个目标，目标是 描述这一新策略的特征，并为使用该方法进行选择性分析提供原理证明 RA在疾病中的操纵：在目标1中，我们将首先描述一种新的反应性星形胶质细胞诱导的 Cre转基因策略在脑疾病中选择性操纵RA在目标2中，我们将使用 选择性消除RA或将其重新编程为非反应性星形胶质细胞的新方法 在癫痫发展的不同阶段。我们的工作将提供新的知识，亲- 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。的理由 一项提议的研究是，对反应性细胞类型在疾病中的作用的新认识是一个重要目标， 来开发更有效的治疗方法我们预计，这项研究将转化为- 我们将向研究界介绍一种强大的新策略，以调查 反应性星形胶质细胞在任何神经系统疾病或紊乱。

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.