Molecular Mechanisms of Sleep Responses to Viral Infection

描述（由申请方提供）：流感病毒诱导的脑调节急性期反应（APR）包括非快速眼动睡眠（NREMS）持续时间延长。这些反应的分子途径仍在研究中，涉及的大脑解剖学途径也是如此。尽管流感PR 8病毒被认为是非嗜神经性的，但最近我们发现，在鼻内攻击后，病毒定位于嗅球（OB）并经历至少部分复制，如通过OB中的正义病毒RNA的表达所证明的，并上调OB和下丘脑（HT）细胞因子表达。我们研究了OB-HT通路通过分子步骤调节APR的假设，这些分子步骤涉及OB中的病原体模式识别受体，它们诱导OB中的白细胞介素-1（IL-1）相关分子。 OB和HT和HT IL 1/生长激素释放激素（GHRH）机制。初步数据; a）表征减弱APR的脑特异性IL 1受体辅助蛋白（AcPb），B）呈现仅在神经元上表达IL 1 I型受体（ILRI）的转基因小鼠，和c）显示缺乏GHRH受体的小鼠在病毒攻击后睡眠较少，不像任何其它小鼠;先前我们显示GABA能HT神经元对IL 1和GHRH都是可接受的。我们提出了三个目标，将澄清的作用，OB-HT通路在APR睡眠反应。目的1验证AcPb减弱APR-IL 1和睡眠对病毒攻击的反应的假设。目的2检验PR-8启动APR睡眠反应依赖于ILRI的OB胶质表达的假设。目的3测试的假设，HT-GHRH/GHRH受体机制是至关重要的流感引发的睡眠成分的APR. We开发的动物模型，首次允许确定的作用，脑特异性细胞因子信号传导机制，AcPb，在神经免疫炎症过程。我们描述了ILRI在神经元和神经胶质细胞上的表达在病毒诱导的APR睡眠反应中的相对贡献。我们利用自发突变导致GHRH受体无功能的小鼠来阐述导致APR睡眠反应的OB-HT细胞因子/GHRH机制。预期结果将表征OB参与APR的启动，从而为药物治疗提供一个新的容易获得的靶点，从而将基础研究快速转化为临床研究。

DESCRIPTION (provided by applicant): Influenza virus-induced brain-regulated acute phase responses (APR) include enhanced duration of non-rapid eye movement sleep (NREMS). The molecular pathways for these responses remain under investigated as do the brain anatomical pathways involved. Although influenza PR8 virus is considered non-neurotropic, recently we showed that upon intranasal challenge the virus localizes to the olfactory bulb (OB) and undergoes at least partial replication, as evidenced by expression of positive sense viral RNA in the OB, and up-regulates OB and hypothalamic (HT) cytokine expression. We investigate the hypothesis that the OB-HT pathway modulates the APR via molecular steps involving pathogen pattern recognition receptors in the OB, their induction of interleukin-1(IL1)-related molecules in the OB and HT and HT IL1/growth hormone releasing hormone (GHRH) mechanisms. Preliminary data; a) characterize a brain-specific IL1 receptor accessory protein (AcPb) that attenuates APRs, b) present a transgenic mouse expressing the IL1 type I receptor (ILRI) only on neurons, and c) show that mice lacking the GHRH receptor sleep less after viral challenge unlike any other mouse; previously we showed that GABAergic HT-neurons are receptive for both IL1 and GHRH. We propose three aims that will clarify the role of the OB-HT pathway in APR sleep responses. Aim 1 tests the hypothesis that AcPb attenuates the APR-IL1 and sleep responses to viral challenge. Aim 2 tests the hypothesis that PR-8- initiation of the APR sleep response is dependent upon OB glial expression of the ILRI. Aim 3 tests the hypothesis that HT-GHRH/GHRH receptor mechanisms are critical to the flu-initiated sleep component of the APR. We develop an animal model that for the first time allows determination of the role of a brain-specific cytokine signaling mechanism, AcPb, in neuro-immune inflammatory processes. We characterize the relative contribution of the ILRI expression on neurons vs. glia in the APR sleep responses induced by virus. We make use of mice with a spontaneous mutation resulting in non-functional GHRH receptors to elaborate the OB-HT cytokine/GHRH mechanisms leading to APR sleep responses. Anticipated results will characterize OB involvement in the initiation of the APR and thereby provide a new readily accessible target for drug therapy and thus for the rapid translation of basic research to the clinic.