Internal State Sensing Via The Gut-Brain Axis

项目总结 代谢失调是包括糖尿病在内的许多年龄相关性疾病的核心节点， 心血管疾病、癌症和神经退化，更广泛地说，被认为会加速衰老 进程。两个器官系统对感觉信息进行解码，以控制全身的能量新陈代谢： 中枢神经系统和肠道。我们如何调节我们的新陈代谢和大脑之间的相互作用 而这个过程中的内脏是生物学和医学中尚未回答的主要问题。我的长期目标是 实验室是为了了解大脑和肠道之间的神经内分泌通讯机制，以及 这一过程中的缺陷导致了能量失调的疾病。我们使用线虫模型来制作我们的 Work，一个非常有用的系统，可以绘制能量平衡电路并可视化生活中的肠道-脑轴 动物。我的实验室已经在大脑中发现了一个神经元回路，它整合了来自 并通过速激肽大脑到肠道的信号通路推动全身性脂肪减少。令人惊讶的是， 我们发现，肠道脂肪状态调节了这个回路中分泌速激肽的神经元，这表明 内部营养状态信息直接从肠道传递到大脑。一种遗传筛查 内感分子揭示了两个肽：INS-7，胰岛素/松弛素超家族的成员，以及NLP-7， 胆囊素/胃泌素家族的成员。我们的中心假设是肠脑多肽在体内 来自肠道的状态信息来调整神经元反应并控制神经的程度 系统能够调节全身的新陈代谢和行为。目标1.解码肠道信号对 控制身体脂肪的感觉神经元。我们将阐明INS-7信号转导的分子机制 改变感觉神经元特性以改变全身新陈代谢。目标2.定义直觉到大脑的信号 潜在的依赖于国家的内部觅食行为。我们将确定NLP-7通过哪些机制从 肠道调节食物的寻找，并提供肠道反应的内感神经元的功能图谱。目标3. 破译肠道感觉和代谢功能与肠道内分泌耦合的机制 分泌物。我们已经开发了可视化和量化活动物体内分泌肽的方法。 我们将利用这种能力进行基因筛查，并定义分子途径，通过这些途径 对体内营养和脂肪状态的感知调节着肠道内分泌肽的释放。这样做的目的是 应用是破译分子和内分泌机制，通过这些机制，来自 肠道被整合到神经元的感觉回路中，以及它是如何影响脂肪代谢和觅食的 行为。在这样做的过程中，我们将定义肠道-脑轴的核心细胞和分子成分。其他 预期的结果是，我们将提供线虫的第一个感官和分子特征 肠道内分泌细胞。我们希望我们的发现能揭示出对肠道-脑轴的新见解。 以及它在年龄依赖性疾病中的作用。

PROJECT SUMMARY Metabolic dysregulation is a central node underlying many age-dependent diseases including diabetes, cardiovascular disease, cancer and neurodegeneration, and more generally, is thought to accelerate the aging process. Two organ systems decode sensory information to control energy metabolism throughout the body: the central nervous system, and the gut. How we regulate our metabolism and the interplay between the brain and the gut in this process are major unanswered questions in biology and medicine. The long-term goal of my laboratory is to understand mechanisms of neuroendocrine communication between the brain and the gut, and the defects in this process that lead to diseases of energy dysregulation. We use the C. elegans model for our work, a tremendously useful system to map energy balance circuits and visualize the gut-brain axis in living animals. My lab has identified a neuronal circuit in the brain that integrates sensory information from the environment, and drives systemic fat loss via a tachykinin brain-to-gut signaling pathway. In a surprising twist, we find that intestinal fat status modulates the tachykinin-secreting neurons in this circuit, suggesting that internal nutrient state information is relayed directly from the gut, back to the brain. A genetic screen for interoceptive molecules revealed two peptides: INS-7, a member of the insulin/relaxin superfamily, and NLP-7, a member of the cholecystokinin/gastrin family. Our central hypothesis is that gut-brain peptides relay internal state information from the intestine to tune neuronal responses and control the extent to which the nervous system is able to modulate whole-body metabolism and behavior. Aim 1. Decoding the effects of gut signals on sensory neurons that control body fat. We will elucidate the molecular mechanisms by which INS-7 signaling modifies sensory neuron properties to alter whole-body metabolism. Aim 2. Defining gut-to-brain signals underlying internal state-dependent food-seeking behavior. We will identify mechanisms by which NLP-7 from the gut regulates food-seeking and provide a functional map of gut-responsive interoceptive neurons. Aim 3. Deciphering mechanisms by which gut sensory and metabolic functions are coupled to enteroendocrine secretions. We have developed methodologies to visualize and quantify secreted peptides in living animals. We will harness this capability to conduct a genetic screen and define the molecular pathways by which the sensing of internal nutrient and fat status regulates the release of gut endocrine peptides. The objective of this application is to decode the molecular and endocrine mechanisms by which interoceptive information from the gut is integrated into the neuronal sensory circuits, and how it influences lipid metabolism and food-seeking behavior. In so doing, we will define the core cellular and molecular components of the gut-brain axis. Other expected outcomes are that we will provide the first sensory and molecular characterization of the C. elegans gut enteroendocrine cells. We expect our findings to reveal fundamental new insights into the gut-brain axis and its role in age-dependent illnesses.