Harnessing Innervation to Promote Pancreatic Islet Function

利用神经支配促进胰岛功能

• 批准号: 9453678
• 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
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9453678
• 关键词: Academia; Afferent Neurons; Anatomy; Autonomic nervous system; Axon; Beta Cell; Blood Circulation; Blood Vessels; Blood flow; Brain; Calcitonin Gene-Related Peptide; Cells; Chronic; Cochlear Implants; Data; Devices; Diabetes Mellitus; Diabetic Autonomic Neuropathy; Diabetic mouse; Disease; Electric Stimulation; Electrodes; Endocrine; Eye; Glucose; Goals; Government Agencies; Health; Human; Human body; Industry; Injury; Insulin; Intervention; Islets of Langerhans; Islets of Langerhans Transplantation; Knowledge; Laboratories; Life; Measures; Mission; Modeling; Monitor; Morbid Obesity; Mus; Nerve; Nervous system structure; Neurons; Nodose Ganglion; Non-Insulin-Dependent Diabetes Mellitus; Organ; Organism; Pacemakers; Pancreas; Pattern; Pericytes; Peripheral; Permeability; Physiological; Plasma; Play; Property; Regulation; Research; Rheumatoid Arthritis; Role; Seminal; Sensory; Slice; Sphincter; Structure of beta Cell of islet; Substance P; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; Transplantation; United States National Institutes of Health; Vascular Permeabilities; Work; afferent nerve; autonomic nerve; base; blood glucose regulation; genetic approach; glucose metabolism; improved; in vivo; in vivo imaging; injured; insulin secretion; islet; mouse model; nerve supply; neuronal cell body; neuroregulation; neurotransmitter release; non-invasive monitor; pancreatic islet function; prevent; reinnervation; response; role model

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 insulin 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 beta cell 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 insulin secretion. Recent anatomical studies show that sympathetic and sensory nerves innervate the human islet, but parasympathetic innervation is sparse. Importantly, these nerves do not contact beta cells directly but densely innervate the islet vasculature. We therefore hypothesize that autonomic nerves control blood flow and vascular permeability to adjust insulin release into the bloodstream. The rationale for the proposed research is that these mechanisms of nerve action could be intervention targets for neuromodulation in human beings, which is relevant to the mission of the NIH. Guided by preliminary data, our hypothesis will be tested by pursuing two specific aims: (1) determine the functional role of sympathetic innervation for insulin secretion, and (2) determine the functional role of sensory nerves for insulin secretion. Under the first aim, we will test that sympathetic nerves target vascular pericytes to change blood flow. We will transplant human and mouse islets into the eye of diabetic mice. In the eye, islet grafts restore normoglycemia and can be monitored non-invasively. Importantly, islet grafts are revascularized and reinnervated in patterns that resemble those of islets in the pancreas. We will stimulate, inhibit, and ablate sympathetic input to islet grafts and determine the effects on islet blood flow and simultaneously measure the effects on insulin plasma levels and glycemia. We will also test whether chronic activation of sympathetic nerves prevents the derangement of islet vasculature in mouse models of type 2 diabetes. Under the second aim, we will test that sensory nerves respond to local perturbations in the islet microenvironment to change the vascular permeability. To determine what activates sensory nerves in the islet, we will use mice that express functional indicators in sensory neurons and measure activity in nerve terminals in the islet in living pancreas slices and in vivo in neuronal cell bodies of the nodose ganglion after stimulating or injuring the islet. We will also activate sensory nerve chronically to test the impact on islet health in mouse models of type 2 diabetes. The proposed research is significant because the research plan takes into account the innervation pattern of the human islet and uses those aspects of mouse islet innervation that are representative of the human situation. Knowing how nerves control insulin secretion is crucial to propose neuromodulation as a therapeutic approach 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， 一部分是通过调节胰岛的胰岛素分泌。用电极刺激自主神经 最近被认为是一种潜在的治疗疾病的方法（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，胰腺β细胞被认为是神经调节的主要靶标。 然而，为了提出神经电刺激治疗糖尿病，必须了解胰岛细胞如何分泌胰岛素。 神经影响β细胞的胰岛素分泌。本申请的目的是确定 神经用来控制胰岛素分泌的机制。最近的解剖学研究表明， 感觉神经支配人胰岛，但副交感神经支配很少。重要的是，这些神经 不直接接触β细胞，但密集地支配胰岛脉管系统。因此，我们假设， 自主神经控制血流和血管渗透性以调节胰岛素释放到血流中。 这项研究的基本原理是，这些神经作用机制可能是干预目标 用于人类的神经调节，这与NIH的使命有关。根据初步数据， 我们的假设将通过追求两个具体目标来检验：（1）确定交感神经的功能作用， 胰岛素分泌的神经支配，和（2）确定感觉神经对胰岛素分泌的功能作用。 在第一个目标下，我们将测试交感神经靶向血管周细胞以改变血流。我们将 将人类和小鼠的胰岛移植到糖尿病小鼠的眼睛中。在眼中，胰岛移植物恢复正常 并且可以非侵入性地监测。重要的是，胰岛移植物的血运重建和神经再支配的模式 类似于胰腺中的胰岛。我们将刺激、抑制和消融对胰岛的交感神经输入， 并测定对胰岛血流量的影响，同时测量对胰岛素血浆的影响 水平和水平。我们还将测试交感神经的慢性激活是否会阻止 2型糖尿病小鼠模型中胰岛血管紊乱。在第二个目标下，我们将测试 感觉神经对胰岛微环境中的局部扰动作出反应，以改变血管张力。 磁导率为了确定是什么激活了胰岛中的感觉神经，我们将使用表达功能性 感觉神经元中的指示剂，并测量活胰腺切片中胰岛中神经末梢的活性， 在体内，在刺激或损伤胰岛后，在结状神经节的神经元细胞体中。我们还将启动 慢性感觉神经，以测试对2型糖尿病小鼠模型中胰岛健康的影响。拟议 这项研究意义重大，因为研究计划考虑到了人类胰岛的神经支配模式。 并使用了小鼠胰岛神经支配的那些方面，这些方面代表了人类的情况。知道如何 神经控制胰岛素分泌对于提出神经调节作为糖尿病的治疗方法至关重要。