Neuronal and molecular mechanisms underlying neural regulation of innate immunity

项目摘要 对病原体感染的免疫反应不足或过度是疾病的主要原因。渐增 有证据表明，神经系统调节免疫系统，以帮助维持免疫力 动态平衡。然而，这一规定的确切机制在很大程度上是未知的。虽然很多方面 在复杂的哺乳动物系统中，很难剖析神经对免疫的调节，线虫 秀丽隐杆线虫因其简单、明确的神经而成为此类研究的极佳模式生物。 免疫系统和免疫系统在几个关键方面类似于人类的先天免疫系统。通过 利用线虫，我们证明了神经递质章鱼胺从两个中间神经元释放 被命名为RIC与G蛋白偶联受体OCTR-1结合，OCTR-1反过来在感觉ASH中发挥作用 抑制非神经组织中的先天免疫反应的神经元。我们建议解剖神经元和 这一八胺能免疫抑制途径的分子机制。我们将确定在哪里 免疫调节信号起源于OCTR-1神经回路，信号是如何从该回路传递出去的 对于非神经组织，非神经组织中的哪些分子介导了先天免疫反应，以及 线虫体内章鱼胺水平是如何调节的，以应对病原体的感染。成功完成 将为理解神经元和分子机制提供重要的新数据。 哺乳动物先天免疫的潜在神经控制。因为过度的先天免疫反应 与人类健康状况有关，如克罗恩病、类风湿性关节炎、动脉粥样硬化、糖尿病和 阿尔茨海默病，八胺能免疫抑制通路可用于治疗 优势。

Project Summary Insufficient or excessive immune responses to pathogen infection are major causes of disease. Increasing evidence indicates that the nervous system regulates the immune system to help maintain immunological homeostasis. However, the precise mechanisms of this regulation are largely unknown. While many aspects of neural regulation of immunity are difficult to dissect in complex mammalian systems, the nematode Caenorhabditis elegans is an excellent model organism for such studies due to its simple, well-defined nervous system and an immune system that resembles the human innate immune system in several key respects. By using C. elegans, we demonstrated that neurotransmitter octopamine released from two interneurons designated as RIC binds to a G protein-coupled receptor OCTR-1, which, in turn, functions in the sensory ASH neurons to suppress innate immune response in non-neural tissues. We propose to dissect the neuronal and molecular mechanisms of this octopaminergic immuno-inhibitory pathway. We will determine where the immuno-modulatory signals originate in the OCTR-1 neural circuit, how the signals are relayed from the circuit to the non-neural tissues, what molecules in the non-neural tissues mediate innate immune responses, and how octopamine level is regulated in C. elegans in response to pathogen infection.  The successful completion of this work will provide significant new data necessary to understand the neuronal and molecular mechanisms underlying neural control of innate immunity in mammals. As excessive innate immune responses have been linked to human health conditions such as Crohn's disease, rheumatoid arthritis, atherosclerosis, diabetes and Alzheimer's disease, the octopaminergic immuno-inhibitory pathway can be exploited to therapeutic advantage.