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。增加 有证据表明，神经系统调节免疫系统，以帮助维持免疫系统。 体内平衡然而，这种调节的确切机制在很大程度上是未知的。虽然许多方面 在复杂的哺乳动物系统中，神经调节免疫的作用很难分解， 秀丽隐杆线虫由于其简单、明确的神经元结构， 系统和免疫系统在几个关键方面类似于人类先天免疫系统。通过 利用C. elegans，我们证明了从两个中间神经元释放的神经递质章鱼胺， RIC结合G蛋白偶联受体OCTR-1，OCTR-1又在感觉ASH中起作用 神经元抑制非神经组织中的先天免疫应答。我们建议解剖神经元， 这种章鱼胺能免疫抑制途径的分子机制。我们将确定 免疫调节信号起源于神经回路，信号是如何从回路传递到神经回路的。 非神经组织，什么分子介导非神经组织中的先天免疫反应，以及如何介导 章鱼胺水平在C.线虫对病原体感染的反应。圆满完成 这项工作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。由于过度的先天免疫反应已经 与人类健康状况如克罗恩病、类风湿性关节炎、动脉粥样硬化、糖尿病和 阿尔茨海默病，章鱼胺能免疫抑制途径可用于治疗 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 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 neural circuit, how the signals are relayed from the circuit to the non-neural tissues, what molecules mediate innate immune responses in the non-neural tissues, 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.