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 代谢失调是一种基本的许多年龄依赖性疾病，包括糖尿病， 心血管疾病，癌症和神经变性，更普遍地被认为可以加速衰老 过程。两个器官系统解码感官信息以控制整个身体的能量代谢： 中枢神经系统和肠道。我们如何调节新陈代谢和大脑之间的相互作用 在此过程中的肠道是生物学和医学中的主要问题。我的长期目标 实验室要了解大脑与肠道之间神经内分泌交流的机制，以及 在此过程中导致能量失调疾病的缺陷。我们将秀丽隐杆线虫模型用于我们的 工作，这是一个非常有用的系统，用于绘制能量平衡电路并可视化生命中的肠道轴 动物。我的实验室已经确定了大脑中的神经元电路 环境，并通过旋转金蛋白脑对肠道信号通路驱动系统性脂肪损失。令人惊讶的是 我们发现，肠脂肪状态调节该电路中分泌速素的神经元，这表明 内部营养状态信息直接从肠道中传递到大脑。一个遗传屏幕 互感分子揭示了两种肽：ins-7，胰岛素/松弛素超家族的成员和NLP-7，NLP-7， 胆囊基蛋白/胃癌家族的成员。我们的中心假设是内部肠道肽中继 从肠道到调节神经元反应并控制神经紧张的程度的状态信息 系统能够调节全身代谢和行为。目标1。解码肠道信号对 控制体内脂肪的感觉神经元。我们将阐明INS-7信号传导的分子机制 修饰感觉神经元特性改变全身代谢。目标2。定义肠道信号 基本的内部依赖国家寻求食物的行为。我们将确定NLP-7的机制 肠道调节寻求食物，并提供肠道反应性神经元的功能图。目标3。 肠道感官和代谢功能与肠内内分泌的解密机制 分泌物。我们已经开发了可视化和量化活动物中分泌的肽的方法。 我们将利用这种能力进行遗传筛选并定义分子途径 感知内部营养和脂肪状态可调节肠内内分泌肽的释放。这个目的 应用是解码分子和内分泌机制 肠道被整合到神经元的感觉电路中，以及它如何影响脂质代谢和寻求食物 行为。这样，我们将定义肠道轴的核心细胞和分子成分。其他 预期的结果是，我们将提供秀丽隐杆线虫的第一个感觉和分子表征 肠道内分泌细胞。我们希望我们的发现能够揭示对肠道轴的基本新见解 及其在年龄依赖性疾病中的作用。