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，神经细胞依靠有效的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牛潜水员阵列移动到需要的区域。在神经元中，这些圆锥形包括支持细胞生长的膜成分。信号分子，最终从神经元中释放为细胞间信息；和生长因子，这些因素是从外部环境中进口的，对于细胞存活至关重要。在被称为突触的细胞的专门区域距离制造细胞组件的距离很远的地方，有效和有针对性的运输尤其重要。神经元通信需要突触，并且完全取决于细胞内转运以提供结构和信号蛋白。主动运输中涉及三个主要要素：1）要移动的货物； 2）驱动运动的分子电动机； 3）发生运动的“轨道”。我的研究计划的目的是了解基本沟通和促进生长分子（例如脑衍生的神经营养因子（BDNF））的细胞和分子碱基的目标是突触。我的研究利用显微镜图像和表征活神经元中的主动传输。通过研究活细胞中发生的事件，我们能够分析这种动态生物学过程。例如，我们可以直接测量细胞器的运输，并直接评估Cargos交通的行为，并在突触部位捕获。我们将使用尖端的生化方法（例如运输复合物的质谱法）来补充成像策略，这将使我们能够鉴定出运输调节的分子机制。我的研究计划将对有关神经元中细胞器运输的基本问题产生答案，这些发现可能会为其他秘密细胞类型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信息。此外，轴突运输的破坏可能是几种神经退行性疾病的病因（例如，阿尔茨海默氏症，亨廷顿和肌萎缩性侧面硬化症）。增强健康神经元基本运输的知识最终会影响我们对疾病状态的理解。