Drosophila as a model for brain-gut signaling

项目摘要 鉴于它在动物健康和生存中的核心作用，肠道已经进化出一个复杂的网络 来自各种来源的调节投入，包括免疫学、新陈代谢和微生物学。演奏一首 在这个调控网络中，突出的作用是脑-肠轴，即大脑与大脑之间的双向交流 神经系统和内脏。虽然有几个描述良好的大脑-肠道信号，但确切的机制 并不总是被很好地理解，许多信号，特别是压力信号和那些涉及 微生物群，仍然难以捉摸。 果蝇已经成为一个解开遗传和细胞的强大模型系统 人类疾病的基础，从癌症和神经疾病到肥胖和糖尿病。这个项目寻求 建立果蝇作为研究脑-肠道相互作用的模型系统。苍蝇大脑发出的一个新信号 人们已经发现，肠道会被禁食等新陈代谢压力激活。短神经肽F 哺乳动物神经肽Y(NPY)的近亲神经肽Y(SNPF)参与了这种脑-肠道信号的传递。初步 研究提出了一种模型，其中sNPF由整合压力的一组特定神经元分泌 向内脏发出信号并对其进行神经支配。SNPF信号的功能是维持增强的肠道上皮完整性 应激期；在没有应激期的情况下，肠道失去上皮完整性，导致无节制的炎症 这种反应会耗尽能量储存，导致严重的饥饿敏感性和寿命缩短。 支配肠道的sNPF神经元将被识别并使用 果蝇身上有先进的遗传工具。如果大脑-肠道应激信号模型是正确的，失活 SNPF神经元的缺失应导致上皮完整性的丧失、炎症反应和细胞耗竭。 能源商店。同样，sNPF神经元的激活应该导致上皮完整性的增强和 抵抗细菌挑战，增加能量储存。该模型还预测了sNPF的作用 通过其受体sNPF-R直接作用于肠道。为了测试这一点，sNPF-R水平将专门在 通过RNAi和sNPF-R基因的突变将产生肠道。 这种脑肠信号的发现和验证将使果蝇成为一种遗传模型 应激期间的大脑-肠道信号系统，并为识别新的 哺乳动物大脑-肠道信号的潜在机制。

Project Summary Given its central role in animal health and survival, the gut has evolved a sophisticated network of regulatory inputs from a variety of sources, including immunological, metabolic and microbiotic. Playing a prominent role in this regulatory network is the brain-gut axis, the bi-directional communication between the nervous system and the gut. While there are several well-described brain-gut signals, the exact mechanisms are not always well understood, and many of the signals, particularly stress signals and those involving the microbiome, remain elusive. The fruit fly Drosophila has emerged as a robust model system for unraveling the genetic and cellular basis of human disease, from cancer and neurological disorders to obesity and diabetes. This project seeks to develop Drosophila as a model system to study brain-gut interaction. A novel signal from the fly brain to the gut has been discovered that is activated by metabolic stresses such as fasting. Short Neuropeptide F (sNPF), a relative of mammalian Neuropeptide Y (NPY), is involved in this brain-gut signal. Preliminary studies suggest a model in which sNPF is secreted by a specific set of neurons that integrate the stress signal and innervate the gut. The sNPF signal functions to maintain heightened gut epithelial integrity during periods of stress; in its absence the gut loses epithelial integrity, resulting in an unchecked inflammatory response that depletes energy stores, leading to acute starvation sensitivity and shortened lifespan. The sNPF neurons that innervate the gut will be identified and specifically inactivated using the advanced genetic tools available in Drosophila. If the brain-gut stress signaling model is correct, inactivation of the sNPF neurons should result in the loss of epithelial integrity, inflammatory response and depletion of energy stores. Similarly, activation of the sNPF neurons should lead to enhanced epithelial integrity and resistance to bacterial challenge, and increased energy stores. The model also predicts that sNPF acts directly on the gut via its receptor, sNPF-R. To test this, sNPF-R levels will be knocked down specifically in the gut by RNAi and mutations in the sNPF-R gene will be generated. The discovery and verification of such a brain-gut signal will establish Drosophila as a genetic model system for brain-gut signaling during periods of stress and lay the foundation for identifying novel mechanisms underlying mammalian brain-gut signaling.