Gut-brain axis in metabolic disease

代谢疾病中的肠脑轴

• 批准号: 10667314
• 负责人: RANDY J SEELEY
• 金额: $ 186.09万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10667314
• 关键词: Affect; Amygdaloid structure; Behavioral; Body Weight; Body Weight decreased; Brain; Brain Stem; Calcitonin; Calories; Cells; Cholecystokinin; Development; Eating; Electrophysiology (science); Endocrine; Energy Metabolism; Food; Food Intake Regulation; Foreign Bodies; Gastric Emptying; Gastrointestinal tract structure; Glucose; Goals; Hypothalamic structure; Impairment; Individual; Infectious Agent; Ingestion; Label; Measures; Mediating; Metabolic; Metabolic Diseases; Methods; Molecular; Monitor; Motivation; Nature; Nausea; Neuroanatomy; Neurons; Nucleus solitarius; Nutrient; Obesity; Operative Surgical Procedures; Peripheral; Physiological; Play; Population; Procedures; Program Research Project Grants; Role; Satiation; Sensory; Signal Transduction; Stimulus; Structure of area postrema; Symptoms; System; Target Populations; Techniques; Testing; Therapeutic; Toxin; Work; absorption; bariatric surgery; cell motility; cell type; experience; gastrointestinal function; gut-brain axis; hedonic; hormonal signals; leptin receptor; mouse model; neural; neural circuit; neuronal circuitry; neurotransmission; next generation sequencing; novel therapeutic intervention; obesity treatment; parabrachial nucleus; pharmacologic; programs; response; targeted treatment

Project Summary/Abstract A wide range of evidence points to the critical role that signals from the gut, acting in the CNS, play in the regulation of food intake, body weight and the disposition of metabolic fuels including glucose. Some of the most powerful evidence for the critical nature of this “gut-brain” axis comes from direct manipulations of the GI tract that occur during various bariatric surgical procedures. These procedures are often thought of as “restrictive” or “malabsorptive”, however, it is clear that the potent effects of these procedures to reduce body weight and glucose levels are the product of altering the activity of the gut-brain axis. The important point is that manipulation of the gut via these surgical interventions provides the largest and most sustained weight loss in individuals with obesity compared to any other therapeutic option. Thus a better understanding of the gut-brain axis is crucial for the development of new, less invasive and more scalable solutions to treat obesity. While the importance of the gut-brain axis is clear, our understanding of how this axis works remains incomplete. This program project grant will bring together a range of experiences and technical approaches under a single coordinated project that will allow for rapid understanding of the impact of gut, neural and hormonal signals on their crucial targets within brainstem neural circuitry. To that end, the current projects will utilize advanced neuroanatomical tracing, electrophysiology, activation and silencing of circuits, next generation sequencing and apply all of these methods exclusively in molecularly defined cell-types using a broad range of mouse models we have developed. These approaches will be combined with a range of behavioral and physiological measures of food intake, energy expenditure and GI function. Finally, we will bring to bear advanced surgical approaches that allow for assessment of the impact of bariatric surgery in these mouse models. The ultimate goal of this project is to identify key aspects of how the GI tract impacts these neuronal circuits, the identification of key neuronal populations that are the target of those GI signals and how each population can influence food intake, body weight and regulate GI function. The guiding hypothesis is that the signals generated and the neural circuit engaged by toxins and those by normal presentation of nutrients to the GI tract will be distinct in several key regions of the brainstem. The detailed understanding of these parallel circuits will allow for a better understanding of existing therapies that target the brainstem and the development of entirely new therapeutic strategies that appropriately engage this circuitry in a manner that is similar to what happens after bariatric surgery.

项目摘要/摘要 广泛的证据表明，来自肠道发出信号的关键作用，在中枢神经系统中发挥作用 食物摄入，体重和包括葡萄糖在内的代谢燃料的处置的调节。一些 最有力的证据表明该“肠脑”轴的批判性质来自对GI的直接操纵 在各种减肥手术过程中发生的道。这些程序通常被认为是 然而，“限制性”或“厌食症”，很明显，这些程序减少身体的有效效果 重量和葡萄糖水平是改变肠道轴活动的产物。重要的一点是 通过这些手术干预措施操纵肠道可提供最大，最持续的重量 与任何其他治疗选择相比，肥胖者的损失。更好地理解 肠脑轴对于开发新的，侵入性较小，更可扩展的解决方案以治疗肥胖症至关重要。 虽然肠道轴的重要性很明显，但我们对该轴工作的理解仍然存在 不完整。该计划项目赠款将汇集各种经验和技术方法 在一个协调的项目下，将可以快速理解肠道，神经和 在脑干神经回路中其关键目标上的马信号。为此，当前的项目将 利用先进的神经解剖图，电生理学，激活和沉默的电路，接下来 使用A的生成测序并将所有这些方法专门应用于分子定义的细胞类型中 我们已经开发了广泛的鼠标模型。这些方法将与一系列 食物摄入，能量消耗和胃肠道功能的行为和物理测量。最后，我们会的 带来先进的手术方法，以评估减肥手术对 这些鼠标模型。 该项目的最终目标是确定胃肠道如何影响这些神经元的关键方面 电路，识别是这些GI信号的靶标的关键神经元种群以及如何 人口可以影响食物摄入，体重和调节胃肠道功能。指导假设是 产生的信号以及由毒素和毒素传入的信号和神经电路的正常表现 胃肠道在脑干的几个关键区域将是不同的。对这些平行的详细理解 电路将可以更好地了解针对脑干和发展的现有疗法 全新的治疗策略，这些策略以类似于什么方式适当地参与该电路 减肥手术后发生。