Modulation of Sensory Transmission by Virally Delivered Genes

躯体感觉系统将触觉、温度和疼痛的信息传递给大脑。支配皮肤的神经细胞被称为“一级”神经元，它们将信号发送到脊髓部分，在那里它们与神经元建立功能性连接，称为突触，神经元在脊柱上下传递信息。被称为神经递质的生化化合物由一级细胞释放，以激活或抑制这些目标“二级”细胞，这些重要的信号分子被称为肽。本项目探讨了脑啡肽、神经肽Y （NPY）和降钙素基因相关肽（CGRP）在神经传递中的作用。特定的基因或反义结构将通过一种利用修饰病毒的新方法传递，以增加或减少这些肽在一级感觉神经元中的产生。基因表达的分子分析、感觉的行为分析和药理学操作将决定肽的作用方式，以及细胞膜上的哪些受体分子负责它们的作用。结果有望阐明脑啡肽和NPY如何抑制感觉传递，而CGRP如何促进感觉传递。这个项目的影响将超越简单的体感传递，因为它将阐明在大脑其他部分使用的特定神经递质的作用机制，并且在这里完善的基因传递方法将为研究其他分子成分在神经元功能中的作用提供有力的工具。

The somatic sensory system carries information on touch, temperature and pain to the brain. Nerve cells innervating the skin called 'first-order' neurons send signals to the spinal cord segments, where they make functional connections called synapses to neurons that carry information up and down the spinal column. Biochemical compounds called neurotransmitters are released by the first-order cells to activate or inhibit these target 'second- order' cells, and an important class of these signaling molecules is known as peptides. This project addresses the role of the peptides enkephalin, neuropeptide Y (NPY), and calcitonin-gene related peptide (CGRP) in this neurotransmission. Particular genes or anti-sense constructs will be delivered by a novel methodology utilizing modified viruses, to increase or decrease the production of these peptides in the first-order sensory neurons. Molecular analysis of gene expression, a behavioral assay for sensation, and pharmacological manipulation will determine how the peptides act, and what receptor molecules on the cell surface membranes are responsible for their action. Results are expected to clarify how enkephalins and NPY inhibit sensory transmission, while CGRP facilitates it. This project will have impact beyond simply somatosensory transmission, because it will clarify mechanisms of action for particular neurotransmitters used in other parts of the brain, and the gene-delivery methods to be perfected here will provide a powerful tool to study the roles of other molecular components in neuronal function.