Dissecting the Nutritional Regulation of Feeding Circuits

剖析喂养回路的营养调节

• 批准号: 9984041
• 负责人: Lisa R Beutler
• 金额: $ 14.37万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9984041
• 关键词: Ablation; Address; Anatomy; Animals; Appetite Regulation; Award; Beta Cell; Bite; Brain; Calcium; Calories; Cell Nucleus; Cells; Cholecystokinin; Clinical; Communication; Data; Data Analyses; Dissection; Doctor of Philosophy; Duodenum; Eating; Endocrinology; Ensure; Fatty acid glycerol esters; Feedback; Fellowship; Food; Functional disorder; Gastrointestinal tract structure; Genetic; Glucose; Glucose Clamp; Goals; Homeostasis; Hormonal; Hormones; Hunger; Hypothalamic structure; Image Analysis; Imaging Techniques; Infusion procedures; Ingestion; Injections; Insulin; Internal Medicine; Intestines; Journals; K-Series Research Career Programs; Knowledge; Laboratories; Lead; Leadership; Ligands; Location; Macronutrients Nutrition; Maintenance; Measurement; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolism; Modeling; Molecular; Monitor; Neurons; Neurosciences; Nodose Ganglion; Nutrient; Nutritional; Obesity; Operative Surgical Procedures; Optics; Pathway interactions; Peptides; Peripheral; Pharmacology; Physicians; Play; Population; Portal vein structure; Positioning Attribute; Process; Proteins; Protocols documentation; Publications; Regulation; Research; Research Personnel; Residencies; Resolution; Rodent; Role; Satiation; Scientist; Serotonin; Signal Transduction; Smell Perception; Stomach; Structure of jugular vein; Techniques; Testing; Time; Tissues; Training; Universities; Vagotomy; Washington; Writing; awake; base; career; detection of nutrient; experimental study; feeding; gut-brain axis; hindbrain; in vivo; in vivo monitoring; insulin signaling; jejunum; neural circuit; novel; obesity development; optogenetics; receptor; relating to nervous system; response; sensor; sensory stimulus; skills; sugar; technique development; tool; virtual

PROJECT SUMMARY/ABSTRACT RESEARCH STRATEGY: Communication between the gut and the brain is essential for energy homeostasis, but how this communication is represented in the dynamics of hypothalamic feeding circuitry is unknown. Early studies of the gut-brain axis relied upon indirect measurements of the effects of nutritionally regulated peripheral signals on feeding circuitry. These studies led to a model in which the activity of key hypothalamic hunger neurons – AgRP neurons – fluctuates gradually as the animal's nutritional state changes. With the development of techniques to record the activity of genetically-defined neuronal populations in awake animals, the dynamics of AgRP neurons were recently observed in vivo for the first time. These studies revealed, contrary to the prevailing model, that AgRP neurons are inhibited rapidly when an animal sees or smells food, before it takes a single bite; however, food ingestion is required for maintenance of this inhibition. We have developed a tool combining in vivo monitoring of AgRP neuron dynamics with intragastric nutrient infusion to show for the first time that nutrient delivery to the gut, in the absence of the sensory stimuli normally associated with eating, is sufficient to inhibit AgRP neurons over a time-scale of minutes. This inhibition is independent of the macronutrient composition of the food but depends upon the number of calories ingested. The goal of this proposal is to determine the molecular and circuit-based mechanisms by which each macronutrient inhibits AgRP neurons. This will be accomplished across three aims: to identify the hormonal mediators responsible, to identify the nutrient sensors involved, and to dissect the pathway by which these signals reach AgRP neurons. CANDIDATE/ENVIRONMENT: Dr. Lisa Beutler is a senior fellow in the Division of Endocrinology at UCSF. She recently completed internal medicine residency at UCSF and an MD/PhD at the University of Washington, where she earned her PhD in Dr. Richard Palmiter's laboratory. She is finishing her fellowship research, which is the subject of a first-author publication in the journal Neuron, in Dr. Zachary Knight's laboratory at UCSF. Having gained expertise in in vivo neural recording and advanced rodent surgery, she now seeks to expand her expertise in the lab to include optical circuit dissection, single-cell resolution calcium imaging, and data analysis and programming skills prior to obtaining an independent position as an academic physician-scientist. CAREER DEVELOPMENT: This award will ensure that Dr. Beutler is able to launch her career as an independent investigator armed with a combination of experimental tools that both position her at the cutting edge of her field (calcium-based imaging techniques, optogenetics) and set her apart from others in the field (advanced rodent surgical techniques). Combined with her clinical training in endocrinology, this will make her uniquely poised to address questions that require detailed knowledge of both neural circuitry and peripheral metabolism. This award will also facilitate Dr. Beutler's acquisition of other professional skills required for independence including formal training in scientific writing, leadership, and management.

项目概要/摘要 研究策略：肠道和大脑之间的沟通对于能量稳态至关重要， 但这种交流如何在下丘脑喂养回路的动态中体现尚不清楚。 对肠脑轴的研究依赖于对营养调节作用的间接测量 这些研究得出了一个模型，其中关键的下丘脑活动。 饥饿神经元——AgRP神经元——随着动物的营养状态的变化而逐渐波动。 开发记录清醒动物中基因定义的神经群活动的技术， 最近首次在体内观察到 AgRP 神经元的动态，这些研究表明， 与流行的模型相反，当动物看到或闻到食物时，AgRP 神经元会迅速受到抑制， 在咬一口之前，我们需要摄入食物来维持这种抑制作用。 开发了一种工具，将 AgRP 神经元动态的体内监测与胃内营养输注相结合 首次表明，在没有通常相关的感觉刺激的情况下，营养物质输送到肠道 与进食一起，足以在几分钟的时间范围内抑制 AgRP 神经元，这种抑制与 食物的大量营养素成分，但取决于摄入的卡路里数量。 提议是确定每种常量营养素抑制的分子和基于电路的机制 AgRP 神经元将通过三个目标来实现：识别负责的激素介质， 识别所涉及的营养传感器，并剖析这些信号到达 AgRP 神经元的途径。 候选人/环境：Lisa Beutler 博士是加州大学旧金山分校内分泌科的高级研究员。 她最近在加州大学旧金山分校完成了内科住院医师培训，并在华盛顿大学获得了医学博士/博士学位， 她在 Richard Palmiter 博士的实验室获得了博士学位，目前正在完成奖学金研究。 这是加州大学旧金山分校 Zachary Knight 博士实验室的第一作者发表在《Neuron》杂志上的主题。 在获得了体内神经记录和高级啮齿动物手术方面的专业知识后，她现在寻求扩展 她在实验室的专业知识包括光路解剖、单细胞分辨率钙成像和数据 在获得学术医师科学家的独立职位之前具备分析和编程技能。 职业发展：该奖项将确保 Beutler 博士能够作为一名 独立调查员配备了一系列实验工具，这些工具都将她置于切割位置 其领域的边缘（基于钙的成像技术、光遗传学）并使她在该领域中脱颖而出 （先进的啮齿动物手术技术）结合她在内分泌学方面的临床训练，这将使她 具有独特的能力来解决需要详细了解神经回路和外周知识的问题 该奖项还将促进 Beutler 博士获得新陈代谢所需的其他专业技能。 独立性，包括科学写作、领导力和管理方面的正式培训。