Mechanisms of transport and synaptic capture of dense core vesicles

致密核心囊泡的运输和突触捕获机制

• 批准号: RGPIN-2018-03945
• 负责人: Silverman, Michael
• 金额: $ 3.06万
• 依托单位: Simon Fraser University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=688504
• 关键词: Mechanisms; transport; synaptic; capture; dense

As with cities, nerve cells rely on efficient transport mechanisms to support their development, function, and survival. Active transport systems within the cell move a diverse array of cargos, targeting them to areas where they are needed. In neurons, these cargos include membrane components, which support cell growth; signaling molecules, which are eventually released from the neuron as intercellular messages; and growth factors, which are imported from the external environment and are critical for cell survival. Efficient and targeted transport is particularly important where specialized regions of the cell known as synapses can be quite a distance from the cell body where cellular components are made. Synapses are required for neuronal communication and are wholly dependent upon intracellular transport to deliver structural and signaling proteins. There are three main elements involved in active transport: 1) the cargo to be moved; 2) the molecular motors that drive movement; and 3) the “tracks” on which movement occurs. The goal of my research program is to understand the cellular and molecular bases for how essential communication and growth-promoting molecules, such as brain-derived neurotrophic factor (BDNF), are targeted to synapses. My research utilizes microscopy to image and characterize active transport in living neurons. By studying events as they occur in living cells, we are able to analyze this dynamic biological process. For example, we can measure organelle transport directly, and assess the behavior of cargos trafficked to, and captured at synaptic sites. We will complement our imaging strategies with the use of cutting-edge biochemical methods such as mass spectrometry of transport complexes, which will allow us to identify molecular mechanisms of transport regulation. My research program will yield answers to basic questions concerning organelle transport in neurons, and these findings will likely provide relevant information for transport studies conducted in other secretory cell types, such as those found in the pancreas and adrenal glands. Moreover, disruption of axonal transport is a likely etiology for several neurodegenerative diseases (e.g., Alzheimer's, Huntington's, and amyotrophic lateral sclerosis); strengthening knowledge of basic transport in healthy neurons will ultimately impact our understanding of disease states.

与城市一样，神经细胞依靠运输机制来支持其发育、功能和生存，细胞内的主动运输系统将多种货物运送到神经元中需要的区域，这些货物包括膜成分。支持细胞生长的信号分子，最终作为细胞间信息从神经元中释放；以及从外部环境输入的生长因子，对于细胞的存活至关重要。被称为突触的细胞可以相当与细胞体的距离是神经通讯所必需的，并且完全依赖于细胞内运输来传递结构和信号蛋白。主动运输涉及三个主要元素：1）要移动的货物； 2）驱动运动的分子马达；3）运动发生的“轨道”我的研究项目的目标是了解重要的沟通和生长促进分子（例如脑源性分子）的细胞和分子基础。神经营养因子（BDNF），针对突触。我的研究利用显微镜对活体神经元中的主动运输进行成像和表征，通过研究活细胞中发生的事件，我们能够分析这种动态的生物过程。直接运输，并评估运输到突触位点和在突触位点捕获的货物的行为，我们将使用尖端的生化方法（例如运输复合物的质谱法）来补充我们的成像策略，这将使我们能够识别突触位点的分子机制。运输我的研究计划将为有关神经元细胞器运输的基本问题提供答案，这些发现可能会为在其他分泌细胞类型中进行的运输研究提供相关信息，例如在胰腺和肾上腺中发现的细胞器运输研究。轴突运输可能是多种神经退行性疾病（例如阿尔茨海默病、亨廷顿舞蹈症和肌萎缩侧索硬化症）的病因；加强对健康神经元基本运输的了解最终将影响我们对疾病状态的理解。