The functional impact of pancreatic islet innervation

胰岛神经支配的功能影响

• 批准号: 10462696
• 负责人: Alejandro Caicedo
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462696
• 关键词: Address; Affect; Afferent Neurons; Anatomy; Autonomic nervous system; Axon; Beta Cell; Biology; Blood Glucose; Brain; Brain Stem; Cell physiology; Cells; Data; Development; Diabetes Mellitus; Disease; Duodenum; Eating; Efferent Neurons; Electric Stimulation; Electrodes; Endocrine; Enteral; Feedback; Ganglia; Genetic; Genetic Recombination; Glucagon; Goals; Hormone secretion; In Situ; Insulin; Islet Cell; Islets of Langerhans; Knowledge; Label; Life; Logic; Maps; Measures; Mission; Modeling; Nerve; Neural Pathways; Neuraxis; Neuroanatomy; Neurons; Nodose Ganglion; Nucleus solitarius; Organ; Pancreas; Pancreatic Endocrine Secretion; Pancreatic Hormones; Peripheral; Physiological; Plasma; Population; Property; Protocols documentation; Publishing; Regulation; Research; Role; Sensory; Signal Transduction; Stress; System; Testing; United States National Institutes of Health; Visceral; Work; afferent nerve; autonomic nerve; base; blood glucose regulation; cholinergic; dorsal motor nucleus; glucose metabolism; glucose tolerance; improved; in vivo; insulin secretion; islet; nerve supply; neural circuit; neuronal circuitry; neuroregulation; novel; novel strategies; optogenetics; pancreatic juice; pre-clinical; prevent; response; tool

The three components of the peripheral autonomic nervous system, the parasympathetic, sympathetic and sensory nerves, work together to prevent life-threatening fluctuations in glucose homeostasis. They do so in part by regulating hormone secretion from the pancreatic islet. Stimulating autonomic nerves with electrodes has recently been recognized as a potential way to treat diseases (neuromodulation). Given its central role in glucose metabolism and diabetes, the pancreatic islet is considered a primary target for neuromodulation. To propose electrical stimulation of nerves to treat diabetes, however, it is essential to understand how islet nerves impact insulin secretion from the beta cell. The objective of this application is to determine the mechanisms nerves use to control hormone secretion from the pancreas. Recent anatomical studies show in detail how autonomic nerves innervate the islet, but how exactly autonomic nerves impact hormone secretion from the islet is not known. We hypothesize that parasympathetic, enteric, and sensory neural pathways act through intrapancreatic ganglia to modulate local cholinergic control of islet cell function. The rationale for the proposed research is that there is a need to understand the local mechanisms of autonomic nerve control of hormone secretion from the islet, which is relevant to the mission of the NIH. Guided by preliminary data, our hypothesis will be tested by pursuing two specific aims: (1) the role of pancreas sensory innervation in regulating islet function, and (2) the role of the intrapancreatic ganglion as a signaling hub controlling islet function. Under the first aim, we will test that the vagal sensory innervation of the islet participates in a vagovagal neuronal circuit regulating islet hormone secretion. We will selectively stimulate islet cells with a chemogenetic approach and gain genetic access to activated neurons with the Targeted Recombination in Active Populations (TRAP) system. We will combine TRAP with tools for labeling, tracing, recording, and manipulating neurons in the brainstem activated by islet cell stimulation. Under the second aim, we will test that intrapancreatic ganglia integrate signals from parasympathetic efferent nerves, enteric neurons, and sensory axons to compute an executive summary of gut and brain inputs to adjust the local cholinergic control they exert on islet cells. We will stimulate parasympathetic, enteric and sensory innervation of the ganglion ex vivo and in vivo with chemogenetic and optogenetic tools and measure the effects in intrapancreatic neurons. We will further study how manipulating intrapancreatic neuronal activity affects islet function and glucose metabolism (insulin plasma levels and glycemia). We expect that applying our novel approaches to measure and manipulate pancreas nerve activity will yield important information about how nerves affect islet biology. This contribution is significant because it will provide fundamental knowledge that will complete and revise models about the influence of autonomic nerves on endocrine pancreas function. Once a functional map of islet innervation is available, we will be able to propose neuromodulation to improve islet function in diabetes.

周围自主神经系统的三个组成部分，副交感神经，交感神经和 感觉神经，共同努力，以防止危及生命的波动葡萄糖稳态。他们这样做， 部分通过调节胰岛的激素分泌。用电极刺激自主神经 最近被认为是一种治疗疾病的潜在方法（神经调节）。鉴于其在以下方面的核心作用， 在葡萄糖代谢和糖尿病中，胰岛被认为是神经调节的主要靶点。到 建议电刺激神经来治疗糖尿病，然而，了解胰岛细胞是如何工作的是至关重要的。 神经影响β细胞的胰岛素分泌。本申请的目的是确定 神经用来控制胰腺激素分泌的机制。最近的解剖学研究表明， 详细说明自主神经如何支配胰岛，但自主神经究竟如何影响激素分泌 从小岛是未知的。我们假设副交感神经、肠神经和感觉神经通路起作用， 通过胰内神经节调节胰岛细胞功能的局部胆碱能控制。的理由 建议的研究是，有必要了解自主神经控制的局部机制， 从胰岛分泌激素，这与NIH的使命有关。根据初步数据，我们 将通过追求两个具体目标来检验这一假设：（1）胰腺感觉神经支配在 调节胰岛功能，以及（2）胰内神经节作为控制胰岛功能的信号中枢的作用 功能在第一个目标下，我们将测试胰岛的迷走神经感觉神经支配参与了一个 调节胰岛激素分泌的迷走神经回路。我们将选择性地刺激胰岛细胞， 化学遗传学的方法，并获得基因访问激活的神经元与靶向的破坏， 活动人口（TRAP）系统。我们将联合收割机TRAP与标记、追踪、记录和 操纵脑干中被胰岛细胞刺激激活的神经元。在第二个目标下，我们将测试 胰内神经节整合来自副交感传出神经、肠神经元和 感觉轴突计算肠道和大脑输入的执行摘要，以调整局部胆碱能控制 它们作用于胰岛细胞。我们将刺激副交感神经，肠神经和感觉神经支配的神经节， 体内和体内用化学遗传学和光遗传学工具进行，并测量胰腺内神经元中的作用。 我们将进一步研究如何操纵胰腺内神经元活动影响胰岛功能和葡萄糖 代谢（血浆胰岛素水平和胰岛素水平）。我们希望应用我们的新方法来测量 并操纵胰腺神经活动将产生关于神经如何影响胰岛生物学的重要信息。 这一贡献是重要的，因为它将提供基础知识，将完成和修订 植物神经对胰腺内分泌功能影响的模型。一旦功能图 胰岛神经支配可用，我们将能够提出神经调节以改善糖尿病中的胰岛功能。