Drosophila as a model for brain-gut signaling

项目摘要 鉴于其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输入，包括免疫学、代谢和微生物。发挥 在这个调节网络中，最重要的作用是脑-肠轴，即脑-肠轴之间的双向交流。 神经系统和肠道。虽然有几个描述良好的脑肠道信号，确切的机制， 并不总是很好地理解，许多信号，特别是压力信号和那些涉及 微生物组仍然难以捉摸。 果蝇已经成为一个强大的模型系统，用于解开遗传和细胞 人类疾病的基础，从癌症和神经系统疾病到肥胖和糖尿病。项目的目标是 将果蝇作为研究脑肠道相互作用的模型系统。一种来自果蝇大脑的新信号 已经发现肠道被代谢应激如禁食激活。短神经肽F sNPF是哺乳动物神经肽Y（NPY）的一种亲戚，参与这种脑-肠信号。初步 研究提出了一个模型，其中sNPF是由一组特定的神经元分泌的，这些神经元整合了压力， 信号和神经支配肠道。sNPF信号的功能是在消化过程中维持增强的肠上皮完整性。 压力时期;在没有它的情况下，肠道失去上皮完整性，导致不受控制的炎症反应。 这种反应消耗能量储存，导致急性饥饿敏感性和寿命缩短。 神经支配肠道的sNPF神经元将被鉴定，并使用免疫组织化学方法特异性灭活。 先进的基因工具。如果脑-肠应激信号模型是正确的， 的sNPF神经元应导致上皮完整性的丧失，炎症反应和消耗， 能量储存。类似地，sNPF神经元的激活应导致增强的上皮完整性， 对细菌挑战的抵抗力和增加的能量储存。该模型还预测，sNPF行为 通过其受体sNPF-R直接作用于肠道。为了测试这一点，sNPF-R水平将被敲低， 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确立果蝇作为遗传模型的地位 系统的脑肠道信号在应激期间，并奠定了基础，以确定新的 哺乳动物脑肠道信号传导的潜在机制。

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.