Rapid sugar sensing from gut to brain

项目摘要/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，但 能量代谢和生存，这种过度消费导致了肥胖和糖尿病的猖獗。因此，它是 这对于确定导致糖过量摄入的肠道-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，被发现感知肠道糖并驱动糖 胃口。神经足细胞通过钠-葡萄糖转运体(SGLT)感知糖分。关于肠道的研究最多 糖的感知主要集中在葡萄糖本身的运输能力上，但对糖的感觉知之甚少。 交通工具。在这里，我们将使用一种特定于人SGLTS的抗糖尿病分子来检测它是否 葡萄糖运输或感觉，这是激活神经足细胞糖感应回路所必需的。我的 假说是，在缺乏转运的情况下，糖分感应会激活神经足细胞，从而产生谷氨酸 释放迷走神经和迷走神经活动。因此，我追求以下目标：1)确定是否有具体的 SGLT激活导致神经足细胞谷氨酸释放和2)确定是否有抗糖尿病 分子导致依赖神经足细胞的快速迷走神经活动。我的方法包括神经遗传学 肠道器官的操作和体内外电生理学。这些研究可能会揭示出 调节肠道-大脑对食物选择的快速控制而不干扰维持生命的药理学靶点 糖分吸收。我的联合赞助人Diego Bohórquez博士和David D‘Alessio医学博士是 神经足细胞营养感知和激素信号在肥胖中的作用。与他们的长期- 建立了导师关系的记录，建议的学习和培训计划将为我提供严格的 以肠脑回路为基础的内科科学家职业生涯所需的科学培训和领导技能 作为减肥干预手段的操控。

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.