Glutamatergic neurotransmission in gut neuropod cells

肠道神经足细胞中的谷氨酸神经传递

• 批准号: 10344995
• 负责人: Diego V Bohorquez
• 金额: $ 39.68万
• 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: 2021-09-21 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10344995
• 关键词: Adult; Affect; Animals; Behavior; Behavioral; Brain; Calcium; Cells; Cholecystokinin; Consumption; Cues; Data; Desire for food; Detection; Duodenum; Electrophysiology (science); Endocrine; Enteroendocrine Cell; Epithelial; Epithelial Cells; Event; Foundations; Glutamates; Goals; Hormones; Hour; Human; Image; Ingestion; Intake; Intestines; Knowledge; Label; Link; Mediating; Metabolic Diseases; Metabolic syndrome; Modality; Mucous Membrane; Mus; Nerve; Neuroepithelial Cells; Neurons; Neurophysiology - biologic function; Neurotransmitters; Nutrient; Oral cavity; Outcome; Outcomes Research; Peptides; Pharmacology; Pharmacotherapy; Population; Property; Public Health; Receptor Signaling; Research Project Grants; Resolution; Rewards; Role; SLC2A1 gene; Sensory; Signal Pathway; Signal Transduction; Signaling Molecule; Small Intestines; Sodium; Specificity; Stimulus; Sucrose; Sweetening Agents; Synapses; System; Taste Perception; Testing; Therapeutic; Time; Transcript; Transducers; Vagus nerve structure; base; behavioral phenotyping; body sense; design; detection of nutrient; experimental study; flexibility; gastrointestinal epithelium; glutamatergic signaling; intestinal epithelium; millisecond; neural circuit; neurotransmission; neurotransmitter release; optogenetics; paracrine; preference; promoter; receptor; response; sensor; sugar; sweet taste perception; therapy development; two-photon; vesicular glutamate transporter 1

SUMMARY Despite the clear link between sugar overconsumption and metabolic syndrome, how the gut senses and communicates the presence of sugar to the brain remains unknown. Studies have shown that preference for sugars depends not on their sweet taste in the oral cavity, but rather on their entrance into the intestine. Therefore, understanding how the gut communicates information about ingested sugars could open a new path for pharmacotherapeutics for treating metabolic disease. The mechanisms of sensing nutrients in the gut are thought to involve the slower paracrine and endocrine action of peptides released from enteroendocrine cells. In recent years it has become evident that in addition to their canonical paracrine function, enteroendocrine cells also form synapses with nerves in the underlying intestinal and colonic mucosa. These gut epithelial cells that form synapses are known as neuropod cells. Our overall hypothesis is that glutamatergic neuropod cells in the small intestine transduce sugar stimuli to guide sugar preference. This hypothesis builds on recent observations: 1) the duodenal epithelium contains a population of glutamatergic neuropod cells labeled by the vesicular glutamate transporter 1; 2) vagal nerve firing in response to intraduodenal sugar stimuli depends on glutamatergic signaling; and 3) a mouse's preference for sugar over non-caloric sweetener is abolished by silencing a subset of enteroendocrine cells. The objectives in this application are three-fold: 1) to determine how glutamatergic neuropod cells are activated by sugar; 2) to establish the glutamatergic gut-to-vagus nerve signaling pathway activated by sugars; and 3) to determine the role of glutamatergic neuropod signaling on sugar preference. The outcomes of this research could serve as a foundation to design gut-based pharmacotherapies that seek to curb the desire to consume sugar by targeting the receptors and signaling molecules of glutamatergic epithelial cells.

总结 尽管糖过量消费和代谢综合征之间存在明显联系，但肠道如何感知和 如何将糖的存在传达给大脑仍然是未知的。研究表明， 糖的摄入量并不取决于它们在口腔中的甜味，而是取决于它们进入肠道。 因此，了解肠道如何传达有关摄入糖的信息可能会开辟一条新的道路 用于治疗代谢性疾病的药物治疗。肠道中感知营养物质的机制是 被认为涉及肠内分泌细胞释放的肽的较慢的旁分泌和内分泌作用。 近年来，很明显，除了典型的旁分泌功能外， 细胞还与下面的肠和结肠粘膜中的神经形成突触。这些肠道上皮细胞 形成突触的细胞被称为神经足细胞。我们的总体假设是， 在小肠中，糖的刺激引导糖的偏好。这一假设建立在最近 观察结果：1）十二指肠上皮含有一群标记为 囊泡谷氨酸转运体1; 2）迷走神经放电对十二指肠内糖刺激的反应取决于 糖能信号传导;和3）小鼠对糖超过无热量甜味剂的偏好被消除， 沉默肠内分泌细胞的一个子集。本申请的目的有三方面：1）确定 糖如何激活多巴胺能神经足细胞; 2）建立多巴胺能肠-迷走神经 糖激活的信号通路;和3）确定多巴胺能神经足信号传导对 糖的偏好本研究的结果可作为设计基于肠道的 药物疗法试图通过靶向受体和信号传导来抑制消费糖的欲望 神经元能上皮细胞的分子。