Mechanisms of transport and synaptic capture of dense core vesicles

与城市一样，神经细胞依赖于有效的运输机制来支持它们的发展，功能和生存。单元内的主动运输系统移动各种各样的货物，将它们定向到需要它们的地区。在神经元中，这些货物包括支持细胞生长的膜成分;信号分子，最终从神经元释放为细胞间信息;和生长因子，从外部环境输入，对细胞存活至关重要。高效和有针对性的运输是特别重要的，其中被称为突触的细胞专门区域可以与制造细胞成分的细胞体有相当的距离。突触是神经元通讯所必需的，并且完全依赖于细胞内转运来递送结构和信号蛋白。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”。我的研究计划的目标是了解细胞和分子基础如何基本的通信和生长促进分子，如脑源性神经营养因子（BDNF），针对突触。我的研究利用显微镜成像和表征活神经元中的主动运输。 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。例如，我们可以直接测量细胞器的运输，并评估运输到突触部位并在突触部位捕获的货物的行为。我们将补充我们的成像策略，使用尖端的生化方法，如运输复合物的质谱分析，这将使我们能够确定运输调节的分子机制。我的研究计划将产生关于神经元细胞器运输的基本问题的答案，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那些。此外，轴突运输的中断是几种神经退行性疾病（例如，阿尔茨海默氏症、亨廷顿氏症和肌萎缩侧索硬化症）;加强对健康神经元基本运输的了解将最终影响我们对疾病状态的理解。

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.