The functional impact of pancreatic islet innervation

胰岛神经支配的功能影响

基本信息

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
项目类别：
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

项目摘要

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，防止危及生命的葡萄糖稳态波动。他们这样做是在部分通过调节胰岛的激素分泌来实现。用电极刺激自主神经最近被认为是治疗疾病的潜在方法（神经调节）。鉴于其核心作用葡萄糖代谢和糖尿病中，胰岛被认为是神经调节的主要目标。到建议电刺激神经来治疗糖尿病，但是，了解胰岛如何神经影响β细胞的胰岛素分泌。该应用程序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，以及自主神经到底如何影响激素分泌来自小岛的情况未知。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。理由如下：拟议的研究是有必要了解自主神经控制的局部机制胰岛分泌的激素，这与 NIH 的使命相关。根据初步数据，我们假设将通过追求两个具体目标来检验：（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参与迷走神经元回路调节胰岛激素分泌。我们将选择性地刺激胰岛细胞化学遗传学方法并通过靶向重组获得对激活神经元的遗传访问活跃种群（TRAP）系统。我们将 TRAP 与标记、追踪、记录和识别工具结合起来。操纵由胰岛细胞刺激激活的脑干神经元。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。我们将刺激神经节前的副交感神经、肠神经和感觉神经支配使用化学遗传学和光遗传学工具进行体内和体内实验，并测量对胰腺内神经元的影响。我们将进一步研究操纵胰腺内神经元活动如何影响胰岛功能和葡萄糖代谢（胰岛素血浆水平和血糖）。我们期望应用我们的新颖方法来衡量操纵胰腺神经活动将产生有关神经如何影响胰岛生物学的重要信息。这一贡献意义重大，因为它将提供可完成和修订的基础知识关于自主神经对内分泌胰腺功能影响的模型。一旦功能图如果胰岛神经支配可用，我们将能够提出神经调节来改善糖尿病的胰岛功能。