Rapid sugar sensing from gut to brain

从肠道到大脑的快速糖传感

• 批准号: 10676399
• 负责人: Emily Jean Alway
• 金额: $ 5.27万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676399
• 关键词: Adult; Agonist; American; Antidiabetic Drugs; Bariatrics; Binding; Brain; COVID-19; Cardiovascular Diseases; Cells; Chronic Disease; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; Consumption; Data; Desire for food; Diabetes Mellitus; Diet; Doctor of Medicine; Doctor of Philosophy; Electrophysiology (science); Energy Metabolism; Epithelial Cells; Family; Food; Glucose Transporter; Glutamates; Goals; Health; Hospitalization; Human; In Vitro; Intake; Intervention; Intestines; Knock-out; Leadership; Life; Ligands; Measures; Mediating; Membrane Proteins; Mentors; Mentorship; Metabolism; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Neurobiology; Neurons; Nitrogen; Obesity; Organoids; Oxygen; Perfusion; Pharmacologic Substance; Physicians; Positioning Attribute; Recommendation; Role; Scientist; Sensory; Signal Transduction; Sodium; Structure; Testing; Therapeutic; Time; Training; Transcript; Vagus nerve structure; absorption; career; comorbidity; detection of nutrient; glucose transport; hormonal signals; in vivo; inhibitor; intestinal epithelium; mind control; neurogenetics; novel; pharmacologic; receptor; response; sensor; skills; sugar

PROJECT SUMMARY/ABSTRACT The average American adult consumes over 40 pounds of sugar per year. While sugar intake is necessary for energy metabolism and survival, this overconsumption has led to rampant obesity and diabetes. Therefore, it is critical to determine the gut-brain circuit that drives sugar overconsumption. Recently, specialized sensory cells in the intestinal epithelium, known as neuropod cells, were found to sense intestinal sugars and drive sugar appetite. Neuropod cells sense sugars using sodium-glucose transporters (SGLTs). Most studies on intestinal sugar sensing have focused on glucose transport ability itself, but little is known about sensing in the absence of transport. Here, we will use an anti-diabetic molecule specific to human SGLTs to probe whether it is glucose transport or sensing that is necessary to activate the neuropod cell sugar sensing circuit. My hypothesis is that sugar sensing, in the absence of transport, will activate neuropod cells, causing glutamate release and vagus nerve activity. Therefore, I am pursuing the following aims: 1) to determine whether specific SGLT activation leads to neuropod cell glutamate release and 2) to determine whether an anti-diabetic molecule leads to rapid, neuropod cell dependent vagal activity. My approach includes neurogenetic manipulations of intestinal organoids and in vitro and in vivo electrophysiology. These studies may uncover a pharmacological target for modulating rapid gut-brain control of food choice without perturbing life-sustaining sugar absorption. My co-sponsors, Drs. Diego Bohórquez, Ph.D. and David D’Alessio, M.D., are experts in neuropod cell nutrient sensing and hormone signaling in obesity, respectively. Consistent with their long- established track record of mentorship, the proposed studies and training plan will provide me with the rigorous scientific training and leadership skills necessary for a career as a physician-scientist based on gut-brain circuit manipulation as a bariatric intervention.

项目摘要/摘要 美国成年人平均每年消耗超过40磅的糖。而糖的摄入剂是必需的 能量代谢和生存，这种过度消费导致肥胖和糖尿病猖ramp。因此，是 确定驱动糖过度消费的肠道回路至关重要。最近，专门的感觉细胞 在肠上皮中，被称为神经足类细胞，可以感觉到肠道糖并驱动糖 食欲。神经足类细胞使用钠 - 葡萄糖转运蛋白（SGLTS）感测糖。大多数关于肠道的研究 糖感应集中于葡萄糖传输能力本身，但在不存在的情况下，灵敏度知之甚少 运输。在这里，我们将使用特定于人类sglts的抗糖尿病分子来探测它是否是 激活神经足类细胞糖感应电路所必需的葡萄糖传输或灵敏度。我的 假设是，在没有转运的情况下，糖传感会激活神经脚架细胞，从而导致谷氨酸 释放和迷走神经活动。因此，我正在追求以下目的：1）确定是否具体 SGLT激活会导致神经胶体细胞谷氨酸释放和2）确定抗糖尿病是否是否 分子导致快速的神经脚类细胞依赖性迷走神经活性。我的方法包括神经源 操纵肠癌，体外和体内电生理学。这些研究可能会发现 用于调节食物选择的快速肠道控制的药理目标，而不会扰动生命 糖滥用。我的共同赞助商，博士。 DiegoBohórquez博士医学博士David D’Alessio是专家 肥胖症中的神经足类细胞营养感和马烯信号传导。与他们的长期 拟议的研究和培训计划的既定往绩记录将为我提供严格的 基于肠道赛道的身体科学家所必需的科学培训和领导技能 操纵作为减肥干预。