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; 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.

项目摘要/摘要 研究策略：肠道与大脑之间的交流对于能量稳态至关重要， 但是，在下丘脑进食电路的动态中表示这种通信是未知的。早期的 肠脑轴的研究取决于间接测量营养调节的影响 馈电路上的外围信号。这些研究导致了一个模型，其中关键下丘脑的活性 饥饿神经元 - AGRP神经元 - 随着动物的营养状态的变化，逐渐波动。与 开发技术以记录清醒动物中普遍定义的神经元种群的活性， 最近首次在体内观察到AGRP神经元的动力学。这些研究表明， 与流行模型相反，当动物看到或闻到食物时，AGRP神经元迅速抑制 在一次咬一口之前；但是，维持这种抑制需要食物摄入。我们有 开发了一种将AGRP神经动力学的体内监测与胃内养分输注的工具 在没有感觉刺激的情况下，首次表明营养递送到肠道 在饮食中，足以在几分钟的时间内抑制AGRP神经元。这种抑制与 食物的大量营养素组成，但取决于摄入的卡路里数量。目标的目标 建议是确定每个大量营养素抑制的分子和基于电路的机制 AGRP神经元。这将在三个目标中实现：确定负责的荷尔蒙调解人 确定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UCSF内分泌学系的高级研究员。 她最近在UCSF完成了内科住所，并在华盛顿大学获得了医学博士学位/博士学位 她在理查德·帕尔米特（Richard Palmiter）博士的实验室获得博士学位。她正在完成她的奖学金研究，这是 是UCSF的Zachary Knight博士实验室中的神经元期刊上的第一任作者出版物的主题。 在体内神经记录和高级啮齿动物手术方面获得了专业知识，她现在试图扩展 她在实验室中的专业知识包括光电路解剖，单细胞分辨率钙成像和数据 分析和编程技能在获得学术身体科学家的独立职位之前。 职业发展：该奖项将确保Beutler博士能够启动她的职业 独立研究者配备了各种实验工具的组合，既将她都定位在切割 她的领域边缘（基于钙的成像技术，光遗传学），并将她与现场的其他人区分开 （高级啮齿动物手术技术）。结合她在内分泌学方面的临床培训，这将使她 独特的中毒，以解决需要详细了解神经回路和周围知识的问题 代谢。该奖项还将促进Beutler博士对其他专业技能的收购 独立性，包括科学写作，领导和管理方面的正式培训。