Mechanisms of signaling between the nervous and immune systems.

项目摘要/摘要 痛感(伤害感)和免疫力共同保护动物免受伤害和感染。这个 然而，神经系统和免疫系统通常是在各自的子领域单独研究的 了解它们之间的联系对于治疗慢性疼痛和炎症性疾病至关重要。这 Proposal在这些领域之间架起了桥梁，以了解果蝇中神经元与免疫细胞的通讯方式 模型系统。 在果蝇幼虫中，伤害性感觉的特征是一种刻板的滚动行为，由几个 有害刺激的类型，如热、化学物质和机械力。感觉到有害输入的神经元 (伤害感受器)将幼虫体壁的每一节都铺上瓷砖。一群血细胞居住在外周神经元附近 树枝状结构。在一次有害的挑战之后，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，发现并封装伤口和外来入侵者。伤害性感受器活动 对于启动强大的免疫反应是必要的，这表明有害信息被传递到 当感觉到威胁时，血细胞。 在这项提议中检验的主要假设是，伤害性感受器与血细胞通信。 通过伤害性感受器树突上的信号。哺乳动物的神经源性免疫激活是通过一种 后向传播动作电位触发促炎因子释放的机制 外围终端。利用果蝇可用的精确遗传工具，我的目标是研究这种机制 幼虫伤害性感受器和免疫细胞之间的信号传递。我会调查中枢和外周是否 伤害性通路有助于神经源性免疫反应(目标1)，以及神经免疫信号是否 涉及反向传播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(目标2)。一个长期目标是使用这个系统来识别其他 通过伤害性感受器特异性筛选参与神经免疫通讯的分子(未来目标3)。 这个项目的结果将进一步加深我们对伤害性感受器的促炎作用的理解，以及 伤害性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状况，同时阐明一般情况 尚不清楚的神经生物学原理，如树突状小泡释放和非典型性 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.