Neuronal gut-pancreas axis and its effect on pancreatic islet physiology and insulin secretion

神经元肠胰轴及其对胰岛生理和胰岛素分泌的影响

• 批准号: 10589033
• 负责人: Madina Makhmutova Sokolov
• 金额: $ 7.71万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589033
• 关键词: Affect; Anatomy; Beta Cell; C-Peptide; Carbohydrates; Cell Nucleus; Cholinergic Receptors; Communication; Coupled; Cues; Data; Diabetes Mellitus; Diet; Digestion; Dimensions; Duodenum; Endocrine; Endocrinology; Enteral; Enteric Nervous System; Etiology; Experimental Models; Foundations; Gastroenterology; Gastrointestinal Physiology; Gastrointestinal tract structure; Gene Expression; Gene Expression Profiling; Genomics; Glucose; Goals; Histologic; Hormones; Image; Immunohistochemistry; In Situ; In Situ Hybridization; Infusion procedures; Insulin; Intake; Islets of Langerhans; Laboratories; Light; Link; Liquid substance; Literature; Mentors; Metabolic Diseases; Modeling; Modernization; Molecular; Molecular Profiling; Muscarinic M3 Receptor; Neurons; Nicotinic Receptors; Nutrient; Operative Surgical Procedures; Organ; Pancreas; Pancreatic Endocrine Secretion; Pathway interactions; Pharmacogenetics; Pharmacologic Substance; Physiological; Physiology; Plasma; Play; Process; Property; Regulation; Reporter; Reporting; Research; Research Project Grants; Role; Sensory; Serum; Signal Transduction; Solid; Stomach; Structure of beta Cell of islet; Study models; System; Technology; Testing; Therapeutic; Time; Visualization; Work; anatomical topography; bariatric surgery; blood glucose regulation; cholinergic; cholinergic neuron; gastrointestinal; glucose metabolism; in vivo; insulin regulation; insulin secretion; intravital imaging; islet; nerve supply; neural; novel; pancreas imaging; pancreatic islet function; pancreatic juice; pharmacologic; postsynaptic; response; sensory input; single nucleus RNA-sequencing; success

ABSTRACT The physiology of glucose metabolism is intricately linked to the process of digestion. Sensory and gastrointestinal cues trigger and enhance insulin secretion from the endocrine pancreas even before the serum glucose levels rise, thus priming the system for the upcoming glucose intake. Not surprisingly, most effective modern therapeutic approaches for the diabetes treatment are shifting from being pancreas-centric to being gut- centric and include surgical options (various types of bariatric surgeries), as well as pharmacological targeting of glucoregulatory signals from the gut (incretin therapies). Yet, the full complexity of how the gut regulates pancreatic responses is not fully understood. While most research has focused on the endocrine signals from the gut to the pancreas, little is known about direct neuronal links between the two organs. Such a neuronal link has been described in anatomical studies and is termed entero-pancreatic plexus. Despite this anatomical connection, the physiological role of this plexus remains almost entirely unaddressed. The long-term goal of this research project is to understand the contribution of the entero-pancreatic neuronal plexus to the regulation of pancreatic islet function. The objective of this application is to identify and characterize the molecular and functional features of the entero-pancreatic neuronal network and its effect on the function of the endocrine pancreas. Our preliminary data support the existence of the entero-pancreatic neuronal plexus and demonstrate that luminal infusion of carbohydrates into the gut triggers activation of pancreatic neurons within seconds. I therefore hypothesize that activation of entero-pancreatic neuronal plexus by luminal nutrients stimulates insulin secretion from the pancreatic beta cells via cholinergic signaling mechanisms. I propose that manipulation of the gut-pancreas axis holds a therapeutic potential for the treatment or management of the metabolic diseases and introduces a new dimension for understanding of the gut-pancreas interaction and incretin signaling. I will test my hypothesis by pursuing two specific aims. Aim 1 will identify the molecular expression profile of enteric neurons that project to the pancreas using single nuclei RNA sequencing of traced neurons and determine the histological topography and connectivity of these neurons using immunohistochemistry and in-situ hybridization. Aim 2 will investigate entero-pancreatic connection physiologically using in-vivo Ca2+imaging and fluorescent tracking of insulin secretion in exteriorized pancreas, combined with pharmacogenetic and surgical manipulation of neuronal pathways. The findings of this proposal will bring into light neural gut-pancreas axis, which has a far-reaching impact on the fields of gastroenterology and endocrinology.

摘要 葡萄糖代谢的生理学与消化过程有着错综复杂的联系。感官和 胃肠道信号触发和增强内分泌胰腺的胰岛素分泌，甚至在血清之前 血糖水平上升，从而使系统为即将到来的葡萄糖摄取做好准备。毫不奇怪，最有效的 治疗糖尿病的现代治疗方法正在从以胰腺为中心转向以肠道为中心。 以中心为中心，包括手术选择(各种类型的减肥手术)以及药物靶向 来自肠道的糖调节信号(胰岛素疗法)。然而，肠道调节方式的全部复杂性 胰腺的反应还没有完全被理解。虽然大多数研究都集中在内分泌信号上 胰腺的肠道，对这两个器官之间的直接神经元联系知之甚少。这样的神经元连接 已在解剖学研究中被描述，并被称为肠-胰神经丛。尽管从解剖学上讲 这种神经丛的生理作用几乎完全没有得到解决。的长期目标是 本研究旨在了解肠-胰腺神经丛在调节中的作用。 胰岛功能。本申请的目的是鉴定和表征分子和 肠-胰腺神经网络的功能特点及其对内分泌功能的影响 胰腺。我们的初步数据支持肠-胰腺神经丛的存在，并证明 向肠道内注入碳水化合物会在几秒钟内触发胰腺神经元的激活。我 因此，假设鲁米那营养素激活肠-胰腺神经丛刺激胰岛素 胰岛β细胞通过胆碱能信号机制分泌。我建议操纵 肠-胰轴具有治疗或管理代谢性疾病的潜力， 介绍了一个新的维度，以了解肠道-胰腺相互作用和胰岛素信号。我要测试一下 我的假设是通过追求两个具体目标。目标1将鉴定肠道病毒的分子表达谱 使用追踪神经元的单核RNA测序投射到胰腺的神经元，并确定 免疫组织化学和原位观察这些神经元的组织学形态和连通性 杂交。目的2将使用体内钙成像和生理研究肠-胰腺连接 外置胰腺胰岛素分泌的荧光示踪，结合药物遗传学和外科手术 神经通路的操纵。这项提议的发现将揭示神经肠道-胰腺轴， 这对胃肠病学和内分泌学领域产生了深远的影响。