Regulation of Brain-Derived Neurotrophic Factor in Microglia

小胶质细胞脑源性神经营养因子的调节

• 批准号: 418299-2012
• 负责人: Trang, Tuan
• 金额: $ 2.84万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=573576
• 关键词: Regulation; Brain; Derived; Neurotrophic; Factor

One of the most significant advances in neuroscience research is the realization that neurons are not the only cell type involved in signalling in the central nervous system (CNS). My research focuses on the fundamental biology of how signals are modulated by an understudied class of cells known as microglia, which are resident immune cells in the CNS. The complex interplay between microglia and neurons is increasingly recognized as being essential for shaping and regulating CNS functions. A key signaling molecule released from microglia is brain-derived neurotrophic factor (BDNF), which in the spinal cord is a substance that alters nerve communication. That BDNF released from microglia fundamentally enhances the ability of neurons to transmit peripheral nerve stimuli such as pain is striking, and makes studying the cellular processes that regulate BDNF a pressing issue for understanding the basic human and animal biology of sensory processing. To date, the mechanisms regulating BDNF in microglia are poorly understood; thus, the proposed research program will closely examine key processes in the production of BDNF, the dynamics of BDNF release and the machinery that drives this release in microglia. To dissect the complex intracellular processes, an experimental approach that integrates biochemical, molecular, and imaging approaches will be used in primary and cell line microglia culture systems. The findings of this research have direct functional implications for microglia-neuron communication, and will form a conceptual framework for broader understanding of microglia signalling throughout the CNS. The potential impact is expected to extend beyond sensory biology as microglia are increasingly implicated in diverse processes involved in the programming and wiring of circuits in the brain and spinal cord. In addition, the proposed studies will form an essential part of my overall research program to understand normal and altered microglia biology, as well as to cultivate the training of highly qualified individuals for careers in academia, government and industry.

神经科学研究中最重要的进展之一是认识到神经元并不是唯一参与中枢神经系统（CNS）信号传导的细胞类型。我的研究重点是信号如何被一种被称为小胶质细胞的细胞调节的基础生物学，这类细胞是中枢神经系统中的常驻免疫细胞。小胶质细胞和神经元之间复杂的相互作用越来越被认为是形成和调节中枢神经系统功能的必要条件。小胶质细胞释放的一个关键信号分子是脑源性神经营养因子（BDNF），它在脊髓中是一种改变神经通讯的物质。从小胶质细胞释放的BDNF从根本上增强了神经元传递周围神经刺激（如疼痛）的能力，这是惊人的，这使得研究调节BDNF的细胞过程成为了解人类和动物感觉处理的基本生物学的紧迫问题。迄今为止，小胶质细胞中BDNF的调节机制尚不清楚；因此，拟议的研究计划将密切研究BDNF产生的关键过程，BDNF释放的动力学和驱动小胶质细胞释放的机制。为了解剖复杂的细胞内过程，一种整合生化、分子和成像方法的实验方法将用于原代和细胞系小胶质细胞培养系统。这项研究的发现对小胶质细胞与神经元之间的交流具有直接的功能意义，并将为更广泛地理解整个中枢神经系统的小胶质细胞信号传递形成一个概念框架。由于小胶质细胞越来越多地参与大脑和脊髓回路的编程和布线等多种过程，预计其潜在影响将超出感觉生物学。此外，拟议的研究将成为我整体研究计划的重要组成部分，以了解正常和改变的小胶质细胞生物学，以及培养学术界，政府和工业界的高素质人才。