Mechanisms of transport and synaptic capture of dense core vesicles

与城市一样，神经细胞依靠有效的运输机制来支持它们的发育、功能和生存。细胞内活跃的运输系统将各种不同的货物运送到需要它们的地区。在神经元中，这些物质包括支持细胞生长的膜组件；最终以细胞间信息的形式从神经元释放的信号分子；以及从外部环境输入的对细胞生存至关重要的生长因子。高效和有针对性的运输尤其重要，因为细胞的特殊区域称为突触，可能距离制造细胞组件的细胞体相当远。突触是神经元通讯所必需的，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要素：1)要移动的货物；2)驱动移动的分子马达；3)发生移动的“轨迹”。我的研究计划的目标是了解必要的通讯和促进生长的分子，如脑源性神经营养因子(BDNF)，是如何针对突触的细胞和分子基础。我的研究利用显微镜对活神经元的主动运输进行成像和表征。通过研究发生在活细胞中的事件，我们能够分析这一动态的生物过程。例如，我们可以直接测量细胞器的运输，并评估运输到突触地点并在突触地点捕获的货物的行为。我们将通过使用尖端的生化方法来补充我们的成像战略，例如运输复合体的质谱学，这将使我们能够识别运输调节的分子机制。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，这些发现可能会为其他分泌细胞类型的运输研究提供相关信息，例如在胰腺和肾上腺中发现的分泌细胞。此外，轴突运输中断可能是几种神经退行性疾病(如阿尔茨海默氏症、亨廷顿氏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知识最终将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.