Sensing Dietary Amino Acids from Gut to Brain

摘要 适当的体重管理要求持续摄入营养均衡的饮食。消费 缺乏氨基酸的饮食会导致体重减轻、肌肉萎缩和全身不适。因此， 在寻找食物替代品的过程中，动物会迅速拒绝缺乏氨基酸的食物。赖氨酸是最常见的 食品中有限的氨基酸和最近的报告表明，这种必需氨基酸的快速检测 通过迷走神经发生。然而，迷走神经不能直接接触到消化的产物 并需要细胞发出信号才能完成任务。我的联合赞助商的实验室发现传感器细胞 与神经元突触的肠，现在被称为神经足细胞。神经足细胞通过 神经递质，最近有人提出，神经足细胞发出的5-羟色胺信号迅速 从肠道内传递出显著的信号。我的初步数据显示迷走神经可以迅速 检测赖氨酸，一些肠道感受器细胞专门感知赖氨酸。基于这些发现，我的 中心假说是肠道神经足细胞向迷走神经细胞转导存在必需的 氨基酸通过5-羟色胺。为了测试这一点，提出了两个目标：(1)测试神经足细胞是否必要 用于迷走神经对赖氨酸的快速感觉，以及(2)确定神经脚细胞是否释放5-羟色胺以发出信号 存在必需的氨基酸赖氨酸。我将结合肠道上皮生物学和 神经生物学来解决这些目标。体外测试将测试神经荚细胞和迷走神经之间的相互作用 赖氨酸感觉中的神经元以及注射赖氨酸后神经荚细胞释放的5-羟色胺。在……里面 活体电生理学将决定神经足细胞的重要性(与光遗传学相结合)和 5-羟色胺(当与药理学结合时)对肠道赖氨酸的迷走神经感觉。这些研究是 预计将揭示迷走神经对必需氨基酸赖氨酸的感觉是否通过神经荚细胞发生 释放5-羟色胺。这项提议最终将支持我成为一名独立医生的培训- 胃肠病学和神经生物学研究的交汇点的科学家。我的培训计划包括 在当地和国际会议上展示我的发现，并规划翻译职业生涯 通过与我的指导团队的有组织的会议以及与领先的Gut的正式访谈进行研究- 脑部科学家。在F30的支持下，我将培养成功过渡到 我的博士后培训。

ABSTRACT Proper weight management mandates consistent consumption of nutritionally balanced diets. Consumption of diets insufficient in amino acids leads to weight loss, muscular atrophy and generalized malaise. As such, animals rapidly reject diets lacking amino acids in search for dietary alternatives. Lysine is the most commonly limited amino acid in foods and recent reports demonstrated that rapid detection of this essential amino acid occurs via the vagus nerve. However, the vagus nerve does not have direct access to digested products of food and require signaling from cells that do. My co-sponsor's laboratory has discovered sensor cells in the intestine that synapse with neurons, now known as neuropod cells. Neuropod cells signal through neurotransmitters, and it has recently been proposed that serotonin signaling from neuropod cells quickly conveys salient cues from within the intestine. My preliminary data show that the vagus nerve can rapidly detect lysine and some intestinal sensor cells specifically sense lysine. Building upon these findings, my central hypothesis is that intestinal neuropod cells transduce onto vagal neurons the presence of essential amino acids through serotonin. To test this, two aims are proposed: (1) to test if neuropod cells are necessary for rapid vagal sensing of lysine, and (2) to determine if neuropods cells release serotonin to signal the presence of the essential amino acid lysine. I will incorporate technologies from intestinal epithelial biology and neurobiology to address these aims. In vitro assays will test the interaction between neuropod cells and vagal neurons in lysine sensing as well as serotonin release from neuropod cells following lysine administration. In vivo electrophysiology will determine the importance of neuropod cells (when combined with optogenetics) and serotonin (when combined with pharmacology) in vagal sensing of intestinal lysine. These studies are expected to uncover whether vagal sensing of the essential amino acid lysine occurs through neuropod cell release of serotonin. This proposal will ultimately support my training to become an independent physician- scientist at the intersection of gastroenterology and neurobiology research. My training plan includes presenting my findings at both local and international conferences and planning a career in translational research through structured meetings with my mentoring team as well as formal interviews with leading gut- brain scientists. With the support of this F30, I will develop the requisite skill set to successfully transition into my post-doctoral training.