Neuronal Wnt Signaling and Intestinal Host Defense in Nematodes

线虫中的神经元 Wnt 信号传导和肠道宿主防御

• 批准号: 1656925
• 负责人: Javier Irazoqui
• 金额: $ 31.71万
• 依托单位: University of Massachusetts Medical School
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1656925&HistoricalAwards=false
• 关键词: Neuronal; Wnt; Signaling; Intestinal; Host

The project focuses on the connection between the nervous and immune systems, an exciting area of active investigation. Emerging evidence indicates that the so-called gut-brain-microbiota axis is very important for health in many different organisms. However, understanding how the nervous system can control host defenses against infection is very limited. Specifically, this research focuses on how neurotransmission in the central nervous system controls gene expression associated with host intestinal defenses in response to pathogens by a well-known molecular signaling pathway (Wnt signaling) in nematodes. Results from this study are expected to elucidate a previously unknown mechanism of neural control of intestinal immunity. The study of nematodes is significant because of their ecological ubiquity and because parasitic nematodes cause severe economic loss (for example, soybean cyst nematodes account for $1.5 billion in crop damage each year in the U.S. alone). In addition, the WNT and nervous system signaling that is the focus of this research using nematodes are conserved in other animals, so that this project will lead to fundamental insights that may be relevant to the nervous system and immune responses of vertebrates, including humans. This project integrates basic science research and a hands-on research experience for a high school teacher as a way to provide experience in the conduct of modern biological research and to have that perspective and understanding communicated to high school students.Neural control of innate immunity is an exciting emerging aspect of host defense, about which little is understood. This is especially true of nematodes, which are the most abundant animals on the planet and are widely used model organisms. The central hypothesis of this proposal is that wingless-Int1 (Wnt) signaling in neurons distally controls the expression of host defense genes in the intestinal epithelium via neuroendocrine signaling. The objective of this proposal is to understand this mechanism of neuroimmune regulation, by defining upstream signaling components that relay Wnt signals in neurons, and downstream mechanisms that mediate neuronal communication with the intestinal epithelium, thereby testing the central hypothesis. To achieve this objective, the Principal Investigator will elucidate the relevant neuronal and Wnt pathway component, specifically which Wnt ligands are induced, the signaling components functioning in neurons, and specific neurons that are involved. The second aim is to elucidate the mechanisms by which Wnt-activated neurons communicate with the intestine to elicit the host response. The researcher will identify neuronal signal(s) that may activate the intestinal response, the role of intestinal muscarinic receptors, and transcription factors controlled by acetylcholine. Because of the novelty of the Wnt-acetylcholine axis, this research has the potential to radically influence our understanding of host-microbe interactions in nematodes. In addition, because the Wnt pathway and muscarinic signaling are evolutionarily conserved, this research has high potential to catalyze advances in neuroimmunity in other organisms.

该项目的重点是神经系统和免疫系统之间的联系，这是一个令人兴奋的积极研究领域。新的证据表明，所谓的肠-脑-微生物轴对于许多不同生物体的健康非常重要。然而，对神经系统如何控制宿主防御感染的了解非常有限。具体来说，这项研究重点关注中枢神经系统中的神经传递如何通过线虫中众所周知的分子信号传导途径（Wnt 信号传导）来控制与宿主肠道防御相关的基因表达，以响应病原体。这项研究的结果有望阐明以前未知的肠道免疫神经控制机制。线虫的研究意义重大，因为它们在生态中无处不在，而且寄生线虫会造成严重的经济损失（例如，仅在美国，大豆胞囊线虫每年就造成 15 亿美元的农作物损失）。此外，作为本次线虫研究重点的 WNT 和神经系统信号在其他动物中也是保守的，因此该项目将带来可能与包括人类在内的脊椎动物的神经系统和免疫反应相关的基本见解。该项目将基础科学研究和高中教师的实践研究经验结合起来，为现代生物学研究提供经验，并将这种观点和理解传达给高中生。先天免疫的神经控制是宿主防御的一个令人兴奋的新兴方面，对此我们知之甚少。对于线虫来说尤其如此，线虫是地球上数量最多的动物，也是广泛使用的模式生物。该提议的中心假设是神经元中的 wingless-Int1 (Wnt) 信号通过神经内分泌信号在远端控制肠上皮中宿主防御基因的表达。该提案的目的是通过定义在神经元中传递 Wnt 信号的上游信号成分和介导神经元与肠上皮细胞通讯的下游机制来了解这种神经免疫调节机制，从而测试中心假设。为了实现这一目标，首席研究员将阐明相关的神经元和 Wnt 通路成分，特别是诱导哪些 Wnt 配体、在神经元中发挥作用的信号成分以及所涉及的特定神经元。第二个目标是阐明 Wnt 激活神经元与肠道通讯以引发宿主反应的机制。研究人员将识别可能激活肠道反应的神经元信号、肠道毒蕈碱受体的作用以及乙酰胆碱控制的转录因子。由于 Wnt-乙酰胆碱轴的新颖性，这项研究有可能从根本上影响我们对线虫宿主-微生物相互作用的理解。此外，由于Wnt通路和毒蕈碱信号在进化上是保守的，因此这项研究具有催化其他生物体神经免疫进展的巨大潜力。