Mechanisms of signaling between the nervous and immune systems.

项目总结/摘要 痛觉（伤害感受）和免疫力共同作用，保护动物免受伤害和感染。的 然而，神经系统和免疫系统通常在各自的子领域中单独研究， 了解它们之间的联系对于治疗慢性疼痛和炎性疾病至关重要。这 一项提案将这些领域连接起来，以了解果蝇中的神经元如何与免疫细胞进行交流 模型系统 在果蝇幼虫中，伤害性感受的特征是刻板的滚动行为，由几个 有害刺激的类型，如热，化学品和机械力。感知有害输入的神经元 （伤害感受器）平铺幼虫体壁的每个节段。一群血细胞位于周围神经元附近 树突在有害的攻击后，这些血细胞分裂并分化成成熟的免疫细胞， 然后在血淋巴中循环，寻找并包裹伤口和外来入侵者。伤害感受器活性是 启动强大的免疫反应所必需的，这表明有害信息被传递到 血细胞会受到威胁 在这个提议中测试的主要假设是伤害感受器与血细胞交流 通过伤害感受器树突的信号传递。哺乳动物中的神经源性免疫激活是通过 反向传播动作电位的机制，触发促炎因子的释放， 外围终端利用果蝇中可用的精确遗传工具，我的目标是研究 幼虫伤害感受器和免疫细胞之间的信号传递。我将研究中枢和外周 伤害性通路有助于神经源性免疫反应（目的1），以及神经免疫信号传导是否 涉及向后传播的动作电位和树突状囊泡释放，类似于 哺乳动物的神经源性炎症（目的2）。一个长期目标是利用这一系统来确定额外的 通过伤害感受器特异性筛选神经免疫通讯的分子参与者（Future Aim 3）。 该项目的结果将进一步加深我们对伤害感受器的促炎作用的理解， 伤害感受器诱导免疫反应的机制。这将对我们的 了解和治疗慢性疼痛和炎症性疾病，同时也阐明了一般 神经生物学原理还没有得到很好的理解，如树突状囊泡释放和非规范 动作电位传播

PROJECT SUMMARY/ABSTRACT Pain sensation (nociception) and immunity work together to protect animals from injury and infection. The nervous system and immune system are typically studied separately in their own subfields, however understanding the link between them is critical for the treatment of chronic pain and inflammatory diseases. This proposal bridges these fields to understand how neurons communicate with immune cells in the Drosophila model system. In Drosophila larvae, nociception is characterized by a stereotyped rolling behavior, triggered by several types of noxious stimuli, such as heat, chemicals, and mechanical force. The neurons that sense noxious input (nociceptors) tile each segment of the larval body wall. A population of hemocytes reside near peripheral neuron dendrites. After a noxious challenge, these hemocytes divide and differentiate into mature immune cells which then circulate in the hemolymph to find and encapsulate wounds and foreign invaders. Nociceptor activity is necessary for the initiation of a robust immune response, suggesting that noxious information is transmitted to hemocytes when a threat is perceived. The main hypothesis tested in this proposal is that nociceptors communicate with hemocytes through signaling at nociceptor dendrites. Neurogenic immune activation in mammals occurs through a mechanism of backwards propagating action potentials that trigger the release of proinflammatory factors from peripheral terminals. Using the precise genetic tools available in Drosophila, I aim to investigate the mechanisms of signaling between larval nociceptors and immune cells. I will investigate whether both central and peripheral nociceptive pathways contribute to neurogenic immune responses (Aim 1), and whether neuro-immune signaling involves backwards propagating action potentials and dendritic vesicle release, similar to mechanisms of neurogenic inflammation in mammals (Aim 2). A long-term goal is to use this system to identify additional molecular participants in neuro-immune communication through a nociceptor-specific screen (Future Aim 3). Results from this project will further our understanding of the proinflammatory role of nociceptors, and the mechanisms by which nociceptors induce immune responses. This will have important implications for our understanding and treatment of chronic pain and inflammatory conditions, while also elucidating general neurobiological principles that are not well understood, such as dendritic vesicle release and non-canonical action potential propagation.