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

项目摘要/摘要 在病原体感染后，细胞应激途径和微生物杀死途径迅速 被宿主免疫系统激活。这些途径必须受到严格的监管，因为这是不够的 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着至关重要的作用。然而， 这一规定背后的确切机制仍不清楚。虽然神经的许多方面 在复杂的哺乳动物系统中或在体外，免疫控制是很难剖析的 线虫秀丽线虫已被证明是研究的极佳模式生物 这种控制是由于其简单、明确的神经系统和遗传基因的可及性， 基因组和分子分析。我们最近的研究表明，OCTR-1，一个推定的G 儿茶酚胺蛋白偶联受体在两个感觉神经元ASH和ASI TO中的作用 通过抑制免疫信号通路抑制先天免疫。这些发现突出了 特定基因和神经元在免疫调节中的重要性。两个重要的因素 然而，问题仍然没有得到回答。首先，激活OCTR-1的配体是什么？ 感觉神经元？第二，哪些神经元与ASH和ASI形成电路来控制先天的 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 鉴定OCTR-1配体的多种分子和遗传学方法(S)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依赖神经激活和调节的分子和细胞 信号，这将让我们更好地理解神经系统是如何控制天生的 豁免权。对病原体的先天免疫调节失调与许多 人类的病理状态，如慢性炎症性疾病和自身免疫 疾病。从拟议研究中收集到的信息将有助于制定 更有效地治疗先天免疫疾病。

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.