Internal State Sensing Via The Gut-Brain Axis

通过肠脑轴进行内部状态感知

• 批准号: 10120465
• 负责人: Supriya Srinivasan
• 金额: $ 50.96万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-24 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10120465
• 关键词: Afferent Neurons; Age; Aging; Animals; Back; Behavior; Behavioral Assay; Biological Assay; Biological Models; Biology; Body fat; Brain; Caenorhabditis elegans; Cardiovascular Diseases; Cell physiology; Cells; Cholecystokinin; Communication; Coupled; Cues; Defect; Diabetes Mellitus; Disease; Endocrine; Energy Metabolism; Enteroendocrine Cell; Environment; Esthesia; Family; Fatty acid glycerol esters; Food; Functional disorder; Future; Gastrins; Genes; Genetic Screening; Goals; Health; Heritability; Human; Insulin; Intestines; Knowledge; Laboratories; Lead; Link; Malignant Neoplasms; Maps; Measures; Medicine; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Methodology; Modality; Modeling; Molecular; Molecular Genetics; Nerve Degeneration; Nervous system structure; Neuraxis; Neurons; Neurosecretory Systems; Nutrient; Obesity; Organ; Outcome; Output; Oxygen; Pathway interactions; Peptides; Pharmaceutical Preparations; Physiology; Play; Population Density; Process; Property; Relaxin; Role; Sensory; Signal Pathway; Signal Transduction; Surface; System; Tachykinin; Testing; Time; Tissues; Work; age related; base; body system; combat; design; energy balance; genetic analysis; genetic approach; gut-brain axis; insight; lipid metabolism; member; neural circuit; neuronal circuitry; response; screening; sensory input; sensory mechanism; uptake

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.

项目摘要 代谢失调是许多年龄依赖性疾病（包括糖尿病）的中心环节， 心血管疾病，癌症和神经退行性疾病，更普遍的是，被认为会加速衰老 过程两个器官系统解码感觉信息，以控制整个身体的能量代谢： 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 以及肠道在这个过程中的作用是生物学和医学中尚未解决的主要问题。我的长期目标是 实验室是了解大脑和肠道之间的神经内分泌通讯机制， 这个过程中的缺陷导致能量失调的疾病。我们使用C。elegans模型为我们 工作，一个非常有用的系统，以映射能量平衡电路和可视化的肠道-大脑轴在生活中 动物我的实验室已经确定了大脑中的一个神经元回路，它整合了来自大脑的感觉信息。 环境，并通过速激肽脑至肠信号通路驱动全身脂肪损失。出人意料的是， 我们发现肠内脂肪状态调节了这个回路中的速激肽分泌神经元，这表明， 内部营养状态信息直接从肠道传递回大脑。一种遗传筛查， 内感受分子揭示了两种肽：INS-7，胰岛素/松弛素超家族的成员，和NLP-7， 胆囊收缩素/胃泌素家族的成员。我们的中心假设是肠脑肽传递内部 状态信息从肠道调节神经元的反应和控制的程度， 系统能够调节全身代谢和行为。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， 改变感觉神经元的特性，从而改变全身的新陈代谢。目标二。定义肠道到大脑的信号 潜在的依赖于内部状态的觅食行为。我们将确定NLP-7从 肠道调节食物寻找并提供肠道反应性内感受神经元的功能图。目标3. 肠道感觉和代谢功能与肠内分泌耦合的解密机制 分泌物我们已经开发了可视化和定量活体动物分泌肽的方法。 我们将利用这种能力来进行遗传筛选，并确定基因表达的分子途径。 内部营养和脂肪状态的感知调节肠内分泌肽的释放。的目的 应用程序是解码分子和内分泌机制，通过这些机制， 肠道整合到神经元感觉回路中，以及它如何影响脂质代谢和食物搜寻 行为这样做，我们将确定核心的细胞和分子组成部分的肠-脑轴。其他 预期的结果是，我们将提供第一个感官和分子表征的C。elegans 肠内分泌细胞我们希望我们的发现能够揭示肠-脑轴的基本新见解 及其在年龄依赖性疾病中的作用。