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育、功能和生存。细胞内的主动运输系统将各种各样的货物移动到需要它们的地方。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，最终作为细胞间信息从神经元中释放出来；生长因子是从外部环境中输入的，对细胞存活至关重要。当被称为突触的细胞特化区域距离制造细胞成分的细胞体相当远时，高效和有针对性的运输尤为重要。突触是神经元通信所必需的，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要素：1)要移动的货物；2)驱动运动的分子马达；3)运动发生的“轨迹”。我的研究项目的目标是了解必要的通信和生长促进分子（如脑源性神经营养因子（BDNF））如何靶向突触的细胞和分子基础。我的研究利用显微镜成像和表征活神经元的主动运输。通过研究在活细胞中发生的事件，我们能够分析这个动态的生物过程。例如，我们可以直接测量细胞器运输，并评估运输到突触位点的货物的行为，并在突触位点捕获。我们将利用先进的生化方法，如运输复合物的质谱分析，来补充我们的成像策略，这将使我们能够确定运输调节的分子机制。我的研究项目将为神经元中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，例如胰腺和肾上腺中发现的细胞。此外，轴突运输中断可能是一些神经退行性疾病（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转运的认识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.