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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：
10317476
负责人：
Alejandro Caicedo
金额：
$ 38.38万
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/10317476
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