Neural regulation of innate immunity to pathogen infection in C.elegans

项目总结/摘要 在病原体感染后，细胞应激途径和微生物杀伤途径迅速被破坏。 由宿主免疫系统激活这些途径必须受到严格监管， 或者过度的免疫反应会产生有害的后果。最近的研究表明 神经系统在免疫反应的调节中起关键作用。但 这一规定背后的确切机制尚不清楚。虽然神经系统的许多方面 在复杂的哺乳动物系统或体外， 秀丽隐杆线虫已被证明是一个很好的模式生物研究 这种控制是由于其简单、明确神经系统和遗传的可及性， 基因组和分子分析。我们最近的研究表明，OCTR-1，一个假定的G 儿茶酚胺的蛋白偶联受体，在两个感觉神经元ASH和ASI中起作用， 通过抑制免疫信号通路来抑制先天免疫。这些发现强调了 特定基因和神经元在免疫调节中的重要性。两个重要 然而，问题仍然没有答案。首先，什么是激活OCTR-1的配体， 感觉神经元？第二，哪些神经元与ASH和ASI形成回路，以控制先天性 免疫反应？在目前的提案中，我们试图回答这两个问题。我们将使用一个 多种分子和遗传学方法来鉴定OCTR-1配体并评估其作用 OCTR-1神经回路中的候选神经元。拟议的研究将揭示 参与OCTR-1依赖性神经细胞凋亡的激活和介导的分子和细胞 信号，这将使我们更好地了解神经系统如何控制先天 免疫力对病原体的先天免疫失调与许多疾病有关， 人类的病理状态，如慢性炎症性疾病和自身免疫性疾病 疾病从拟议研究中收集的信息将有助于制定 更有效的治疗先天性免疫疾病的方法

Project Summary/Abstract Upon pathogen infection, cellular stress pathways and microbial killing pathways are rapidly activated by the host immune system. These pathways must be tightly regulated as insufficient or excessive immune responses have deleterious consequences. Recent studies indicate that the nervous system plays a critical role in the regulation of immune responses. However, the precise mechanisms behind this regulation remain unclear. While many aspects of neural control of immunity are difficult to dissect in complex mammalian systems or in vitro, the nematode Caenorhabditis elegans has proven to be an excellent model organism for studying such control due to its simple, well-defined nervous system and accessibility to genetic, genomic, and molecular analyses. Our recent studies demonstrated that OCTR-1, a putative G protein-coupled receptor for catecholamines, functions in two sensory neurons ASH and ASI to suppress innate immunity by inhibiting immune signaling pathways. These findings highlight the importance of specific genes and neurons in the regulation of immunity. Two important questions, however, remain unanswered. First, what is the ligand that activates OCTR-1 in the sensory neurons? Second, which neurons form circuits with ASH and ASI to control the innate immune responses? In the current proposal, we seek to answer both questions. We will use a variety of molecular and genetic approaches to identify OCTR-1 ligand(s) and assess the roles of candidate neurons in the OCTR-1 neural circuit. The proposed studies will uncover molecules and cells involved in the activation and mediation of the OCTR-1-dependent neural signaling, which will give us a better understanding of how the nervous system controls innate immunity. Dysregulation of innate immunity to pathogens has been linked to a number of pathological states in human, such as chronic inflammatory diseases and autoimmune diseases. Information gleaned from the proposed studies will be useful to the development of more effective treatments for innate immune disorders.