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.

项目概要/摘要 美国成年人平均每年消耗超过 40 磅的糖。虽然糖的摄入是必要的 能量代谢和生存，这种过度消耗导致了猖獗的肥胖和糖尿病。因此，它是 对于确定导致糖过度消耗的肠脑回路至关重要。最近，专门的感觉细胞 在肠上皮细胞中，称为神经足细胞，被发现可以感知肠糖并驱动糖 食欲。 Neuropod 细胞使用钠-葡萄糖转运蛋白 (SGLT) 感知糖。大多数研究都是针对肠道 糖传感主要集中在葡萄糖转运能力本身，但对于缺乏葡萄糖转运能力的情况下的传感知之甚少 的运输。在这里，我们将使用人类 SGLT 特异的抗糖尿病分子来探究它是否是 葡萄糖转运或传感是激活神经足细胞糖传感电路所必需的。我的 假设是，在没有运输的情况下，糖感应会激活神经足细胞，导致谷氨酸 释放和迷走神经活动。因此，我追求以下目标：1）确定是否具体 SGLT 激活导致神经足细胞谷氨酸释放，2) 以确定是否具有抗糖尿病作用 分子导致快速的神经足细胞依赖性迷走神经活动。我的方法包括神经遗传学 肠道类器官的操作以及体外和体内电生理学。这些研究可能会揭示一个 调节肠脑对食物选择的快速控制而不干扰生命维持的药理学目标 糖的吸收。我的共同发起人，博士。迭戈·博霍尔克斯博士和 David D’Alessio 医学博士是以下领域的专家 分别是肥胖症中的神经足细胞营养感应和激素信号传导。符合他们长期以来的 已建立的指导记录，拟议的学习和培训计划将为我提供严格的指导 基于肠脑回路的医师科学家职业所需的科学培训和领导技能 操纵作为减肥干预措施。