Neuronal Wnt Signaling and Intestinal Host Defense in Nematodes

该项目侧重于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。新出现的证据表明，所谓的肠-脑-微生物群轴对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，本研究的重点是中枢神经系统的神经传递如何通过线虫中众所周知的分子信号通路（Wnt信号通路）控制宿主肠道防御相关基因表达，以应对病原体。这项研究的结果有望阐明一个以前未知的肠道免疫的神经控制机制。线虫的研究意义重大，因为它们在生态系统中无处不在，而且寄生线虫会造成严重的经济损失（例如，仅在美国，大豆囊肿线虫每年就造成15亿美元的作物损失）。此外，WNT和神经系统信号是本研究使用线虫的重点，在其他动物中是保守的，因此该项目将导致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与高中教师的实践研究经验结合起来，作为提供现代生物学研究经验的一种方式，并将这种观点和理解传达给高中学生。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，关于它知之甚少。线虫尤其如此，它们是地球上数量最多的动物，也是被广泛使用的模式生物。该建议的中心假设是，神经元中的无翼int1 （Wnt）信号通过神经内分泌信号远端控制肠上皮中宿主防御基因的表达。本提案的目的是通过定义神经元中传递Wnt信号的上游信号成分，以及介导神经元与肠上皮通信的下游机制，从而了解神经免疫调节的机制，从而验证中心假设。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，特别是哪些Wnt配体被诱导，神经元中起作用的信号成分，以及涉及的特定神经元。第二个目的是阐明wnt激活的神经元与肠道沟通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由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中宿主-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，因此本研究在催化其他生物的神经免疫进展方面具有很高的潜力。

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.