Regulation of Brain-Derived Neurotrophic Factor in Microglia

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参与中枢神经系统(CNS)信号传递的唯一细胞类型。我的研究集中在信号如何被一类被称为小胶质细胞的研究较少的细胞调制的基础生物学上，小胶质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塑造和调节中枢神经系统功能的关键。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，这一点令人震惊，并使研究调节BDNF的细胞过程成为了解人类和动物感觉加工的基本生物学的紧迫问题。到目前为止，对小胶质细胞中BDNF的调节机制还知之甚少；因此，拟议的研究计划将密切关注BDNF产生的关键过程、BDNF释放的动力学以及驱动小胶质细胞这种释放的机制。为了剖析复杂的细胞内过程，将在原代和细胞系小胶质细胞培养系统中使用一种整合了生化、分子和成像方法的实验方法。这项研究的发现对小胶质细胞-神经元通讯具有直接的功能意义，并将形成一个概念框架，以更广泛地理解整个中枢神经系统的小胶质细胞信号传递。随着小胶质细胞越来越多地参与大脑和脊髓电路的编程和连接的不同过程，潜在的影响预计将延伸到感觉生物学之外。此外，拟议中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，以及培养高素质的个人，以便在学术界、政府和行业就业。

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.