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.

项目总结/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，这种过度消费导致了猖獗的肥胖和糖尿病。因此有 这对确定导致糖摄入过量的肠道-大脑回路至关重要。最近，专门的感觉细胞 在肠上皮中，被称为神经足细胞，被发现可以感知肠道糖并驱动糖 胃口神经足细胞使用钠-葡萄糖转运蛋白（SGLT）感知糖。大多数关于肠道的研究 糖传感主要集中在葡萄糖转运能力本身，但对缺乏葡萄糖转运能力的传感知之甚少 交通工具。在这里，我们将使用一种对人SGLT特异的抗糖尿病分子来探测它是否是 葡萄糖转运或感测是激活神经足细胞糖感测电路所必需的。我 一种假设是，在缺乏转运的情况下，糖的感知将激活神经足细胞，产生谷氨酸盐。 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和2）确定抗糖尿病药物是否 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 用于调节食物选择的快速肠-脑控制而不干扰维持生命的药理学靶点 糖的吸收我的共同赞助人，迭戈·博霍尔奎兹博士和医学博士大卫·达莱西奥是专家在 神经足细胞营养传感和激素信号在肥胖症。与他们长期的- 已建立的导师跟踪记录，拟议的学习和培训计划将为我提供严格的 科学训练和领导技能，作为一个基于肠道-大脑回路的医生-科学家的职业生涯所必需的 操纵作为减肥干预。