Sympathetic-Immune Interface: Central Sites & Function

描述(申请人摘要)：最近的证据表明 白细胞衍生激素(即细胞因子)提供了一个重要的信号转导 通向交感神经回路的途径。然而，涉及的中央通路 在介导交感神经放电(SND)对白介素1β的反应中， 促炎症细胞因子及IL-1的功能意义 贝塔介导的SND反应仍然不明确。这些都很重要 省略是因为详细阐述了免疫系统 改变SND对于理解自主免疫的作用至关重要 生理调节和疾病过程中的相互作用。具体目标1： 确定参与介导SND对IL-1反应的中枢神经部位 贝塔。我们将检验这样的假设：a)不同水平的脊柱上 神经轴介导对IL-1β的区域性选择性SND反应 室旁核神经元在中枢神经系统中起重要作用 前脑依赖的SND对IL-1β的反应，c)延髓腹侧 是介导SND对IL-1β反应的关键脑干部位，以及d) 脑室周围器官是中枢神经回路的一部分。 介导SND对外周IL-1β的反应。具体目标2：确定 IL-1β的靶器官效应。我们假设IL-1β给药 在动脉血流中不会产生均匀的变化，而是区域性的 循环和脾神经传出神经激活诱导细胞因子 增强机体免疫能力的基因表达。 电生理、中枢神经系统微量注射、频域 将使用分析和分子生物学技术来完成这些 学习。这项提案中描述的实验方法将有助于解开 免疫和交感神经系统的调节控制。 最终，这些发现可能为干预策略的设计提供依据 在免疫调节方面促进强健和适当的沟通 免疫系统和神经系统。

DESCRIPTION (Applicant's abstract): Recent evidence indicates that leukocytic-derived hormones (i.e., cytokines) provide an important signaling pathway to sympathetic neural circuits. However, the central pathways involved in mediating sympathetic nerve discharge (SND) responses to interleukin-1 beta, a proinflammatory cytokine, and the functional significance of IL-1 beta-mediated SND responses remain poorly defined. These are significant omissions because the elaboration of mechanisms by which the immune system alters SND is critical for understanding the role of autonomic-immune interactions in physiological regulation and disease processes. Specific Aim 1: To identify central neural sites involved in mediating SND responses to IL-1 beta. We will test the hypotheses that a) different levels of the supraspinal neuraxis mediate regionally-selective SND responses to IL-1 beta, b) paraventricular nucleus neurons are critically involved in mediating forebrain-dependent SND responses to IL-1 beta, c) the ventral lateral medulla is a key brainstem site mediating SND responses to IL-1 beta, and d) circum-ventricular organs are part of the central circuitry involved in mediating SND responses to peripheral IL-1 beta. Specific Aim 2: To determine target organ effects of IL-1 beta. We hypothesize that IL-1 beta administration produces no uniform changes in arterial blood flow to regionally-selective circulations and that activation of splenic nerve efferents induces cytokine gene expression which enhances the immune capability of the organism. Electrophysiological, central nervous system microinjection, frequency-domain analytical and molecular biological techniques will be used to complete these studies. The experimental approach described in this proposal will help unravel the regulatory controls of the immune and sympathetic nervous systems. Ultimately, these findings may allow for the design of intervention strategies in immune regulation fostering robust and appropriate communication between the immune and nervous systems.