Sensing Dietary Amino Acids from Gut to Brain

感知从肠道到大脑的膳食氨基酸

• 批准号: 10535491
• 负责人: Peter Weng
• 金额: $ 4.91万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10535491
• 关键词: Address; Amino Acids; Animals; Arginine; Biology; Biosensor; Body Weight decreased; Brain; Brain region; Calcium; Cells; Circulation; Coculture Techniques; Consumption; Cues; Data; Detection; Diet; Disease Resistance; Electrophysiology (science); Enteroendocrine Cell; Essential Amino Acids; Esthesia; Exposure to; Failure to Thrive; Fellowship; Food; Gastroenterology; Goals; Health; Hour; In Vitro; Individual; International; Interview; Intestinal Content; Intestines; Knowledge; Laboratories; Life; Location; Lysine; Malaise; Mentors; Metabolic Diseases; Metabolism; Methods; Muscle Weakness; Muscular Atrophy; Nerve; Neurobiology; Neurons; Neurotransmitters; Non-Essential Amino Acid; Nutritional; Nutritive Value; Pathway interactions; Patients; Perfusion; Peripheral; Pharmacology; Physicians; Recommendation; Reporting; Research; Rodent; Science; Scientist; Sensory; Serotonin; Serotonin Antagonists; Signal Transduction; Stomach; Structure; Synapses; System; Technology; Testing; Training; Translational Research; Vagus nerve structure; Visceral; Weight maintenance regimen; body sense; career; cellular transduction; combat; dietary; good diet; in vitro Assay; in vivo; intestinal epithelium; meetings; millisecond; nutrition; optogenetics; post-doctoral training; prevent; rapid detection; response; sensor; skills; sugar; symposium

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.

摘要 适当的体重管理要求持续摄入营养均衡的饮食。消费 饮食中氨基酸不足会导致体重减轻、肌肉萎缩和全身不适。因此，在本发明的一个方面， 动物迅速拒绝缺乏氨基酸的饮食以寻找饮食替代品。赖氨酸是最常见的 食品中氨基酸含量有限，最近的报道表明，快速检测这种必需氨基酸 通过迷走神经发生。然而，迷走神经不能直接接触消化产物， 食物，并需要来自细胞的信号。我的共同赞助者的实验室在大脑中发现了传感器细胞 与神经元形成突触的肠，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，血清素信号从神经足细胞迅速 从肠道内传递显著的线索。我的初步数据显示迷走神经可以迅速 检测赖氨酸和一些肠道传感器细胞特异性地感知赖氨酸。基于这些发现，我 中心假设是肠神经足细胞在迷走神经元上存在必需的 从氨基酸到血清素为了验证这一点，提出了两个目标：（1）测试是否需要神经足细胞 用于赖氨酸的快速迷走神经感应，以及（2）确定神经足细胞是否释放5-羟色胺以发出信号， 必需氨基酸赖氨酸的存在。我将结合肠上皮生物学的技术， 神经生物学来实现这些目标。体外试验将测试神经足细胞和迷走神经之间的相互作用。 神经元在赖氨酸感知以及赖氨酸给药后从神经足细胞释放5-羟色胺。在 体内电生理学将决定神经足细胞的重要性（当与光遗传学结合时）， 5-羟色胺（当与药理学结合时）在肠赖氨酸迷走神经感觉中的作用。这些研究 期望揭示迷走神经对必需氨基酸赖氨酸的感受是否通过神经足细胞发生 血清素的释放该提案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交叉研究的科学家。我的训练计划包括 在本地和国际会议上展示我的研究成果，并计划在翻译领域的职业生涯 通过与我的指导团队的结构化会议以及与领导的正式访谈进行研究， 脑科学家在F30的支持下，我将发展必要的技能，成功地过渡到 我的博士后训练