Novel approaches to study microglia physiology and pathology in the intact brain

研究完整大脑中小胶质细胞生理学和病理学的新方法

• 批准号: 8358360
• 负责人: Axel Nimmerjahn
• 金额: $ 288万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358360
• 关键词: Adult; Amyotrophic Lateral Sclerosis; Behavior; Brain; Brain Pathology; Cell Communication; Cells; Central Nervous System Diseases; Complex; Data Analyses; Development; Disease; Environment; Fluorescence; Image Analysis; In Vitro; Knowledge; Microglia; Monitor; Mus; Neurons; Pathology; Physiology; Property; Regulation; Research; Resolution; Rett Syndrome; Role; Signal Transduction; Staining method; Stains; Structure; Synaptic plasticity; abstracting; genetic manipulation; in vivo; insight; minimally invasive; neurogenesis; novel; novel strategies; painful neuropathy; postnatal; public health relevance; tool

DESCRIPTION (Provided by the applicant) Abstract: Microglia are key players in most if not all central nervous system (CNS) disorders including neuropathic pain, Rett syndrome, amyotrophic lateral sclerosis and Nasu-Hakola disease. Recent evidence suggests that these cells also participate in regulation of neurogenesis, circuit remodeling and synaptic plasticity during normal postnatal development, influences they may continue to exert in the adult brain. Despite these vital roles in normal physiology and pathology, we know virtually nothing about these cells' signaling, how it is influenced by local environment and disease, and how it influences other cells and their dynamics in the normal brain. This dearth of knowledge is largely due the inability of in vitro approaches to accurately recapitulate the brain's environment to which microglia are highly sensitive and adaptable and a lack of proper tools to monitor and manipulate microglial cells in vivo. To begin to overcome these limitations we have developed a set of fluorescence staining and genetic manipulation, imaging and data analysis tools for the study of cellular dynamics in the normal brain. These tools have allowed us to reveal, for example, novel forms of astrocytic and neuronal excitation in behaving mice and microglia's surveillance behavior in the healthy adult brain. Building on these approaches we now propose to develop a new set of tools for minimally invasive monitoring and manipulation of microglia in both superficial and deep brain structures. This will allow us to deliver unprecedented insight into these cell's functional dynamics and interactions. Our research therefore has broad implications for our view of microglia, their beneficial and detrimental roles in the healthy and diseased brain and more generally for our ability to uncover complex cell-cell interactions in the normal brain. Public Health Relevance: Microglial cells are involved in onset, progression and/or resolution of essentially all brain pathologies. However, little is known about their properties in the intact brain. We propose to fill this essential gap in our knowledge through development and application of novel research tools.

描述（申请人提供） 摘要：小胶质细胞是大多数（如果不是全部）中枢神经系统（CNS）疾病的主要参与者，包括神经性疼痛，RETT综合征，肌萎缩性侧面硬化症和NASU-Hakola病。最近的证据表明，这些细胞还参与了正常产后发育过程中神经发生，回路重塑和突触可塑性的调节，会影响它们可能继续在成人大脑中施加的。尽管在正常的生理和病理学中起着至关重要的作用，但我们几乎对这些细胞的信号传导，如何受到局部环境和疾病的影响以及它如何影响其他细胞及其在正常大脑中的动态方面一无所知。这种知识的缺乏在很大程度上是由于无法准确概括大脑环境的小胶质细胞高度敏感和适应能力的环境的缺乏，并且缺乏适当的工具来监测和操纵体内的小胶质细胞。为了开始克服这些局限性，我们开发了一组荧光染色和基因操纵，成像和数据分析工具，用于研究正常大脑中细胞动力学的研究。这些工具使我们能够揭示出在健康成人大脑中行为和小胶质细胞的监测行为中的新型星形细胞和神经元激发形式。在这些方法的基础上，我们现在建议开发一套新的工具，用于在浅表和深脑结构中对小胶质细胞的微创监测和操纵。这将使我们能够对这些细胞的功能动态和相互作用进行空前的见解。因此，我们的研究对我们对小胶质细胞的看法具有广泛的影响，它们在健康和患病的大脑中的有益和有害作用，更普遍地对于我们发现正常大脑中复杂的细胞相互作用的能力。 公共卫生相关性：小胶质细胞与所有大脑病理的发作，进展和/或分辨率有关。但是，关于它们完整的特性知之甚少 脑。我们建议通过开发和应用新颖的研究工具来填补我们的知识中的这一基本差距。