Central Control of Pancreatic Islet Function

胰岛功能的中央控制

基本信息

批准号：
9271963
负责人：
Christopher J Rhodes
金额：
$ 46.28万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9271963
关键词：
Acute Address Adenovirus Vector Affect Alpha Cell Anatomy Beta Cell Biochemical Brain Brain region Cell physiology Cells Characteristics Communication Complement Complex Data Diabetes Mellitus Elements Enzymes Epidemic Failure Feedback Foundations Genes Glucagon Glucokinase Glucose Goals Health Homeostasis Hypothalamic structure In Vitro Insulin Insulin Receptor Insulin Resistance Insulin Signaling Pathway Islet Cell Islets of Langerhans Label Lead Leptin Link LoxP-flanked allele Maps Measures Mediating Metabolic Mus Muscarinic M3 Receptor Neuraxis Neurologic Neurons Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Onset of illness Pancreas Peripheral Physiological Pseudorabies Regulation Research Resolution Rodent Signal Transduction Structure of beta Cell of islet Techniques Technology Therapeutic Tracer Transgenic Mice Translating Viral Vector adenoviral-mediated base experimental study gain of function gene function hormone regulation in vivo insight insulin secretion insulin sensitivity insulin signaling islet neglect nerve supply neuronal circuitry novel novel therapeutic intervention pancreatic islet function public health relevance reduce symptoms

项目摘要

DESCRIPTION (provided by applicant): Obesity-linked type 2 diabetes is a major health problem of worldwide epidemic proportions. The onset of the disease is marked by failure of the functional pancreatic islet ß-cell mass to meet metabolic demand, and is thus an insulin insufficient state. It follows that a means to protect and preserve adequate functional ß-cell mass has therapeutic potential for type 2 diabetes. Much is known about nutrient and hormonal regulation of ß-cell function. However, despite it being known for more than 160 years that the central nervous system (CNS) has a significant degree of control over pancreatic islet functions, mechanisms of CNS control over pancreatic ß-cells remain vague. Indeed, the precise regions of the CNS that link to pancreatic islets are unknown. In this proposal it is intended to utilize a novel class of pseudorabies viral vectors (PRV) as retrograde transynaptic neuronal tracers to accurately track the neuronal link between pancreatic islets and specific regions of the CNS in vivo. This will be complemented by several in vivo anterograde-tracing techniques to refine the PRV retrograde tracing. Aim-1 will use both retrograde and anterograde neuronal tracking approaches to reveal a CNS `brain-to-islet topographical map' in mice, at a 5µm-resolution and in 3D. This map will be characterized in detail, particularly to unveil what kind of neuronal cells are within it and to utilize novel anterograde-tracking techniques to identify specific neuronal circuitries that can be activated within this map. In Aim-2 glucose-sensing neurons within the `brain-to-islet map' will be manipulated, using accurate stereotaxic delivery of adenoviral vectors that alter glucokinase activity in specific sub-regions of the hypothalamus. Likewise, in Aim-3, a similar stereotaxic approach will be taken, but aimed at specifically targeting particular hypothalamic insulin-signaling neurons, where insulin receptor and IRS-2 gene function will be manipulated. Then, it will be assessed whether alteration of glucose-sensing and/or insulin-signaling in regions of the CNS which link to pancreatic islets will affect islet cell function in ivo, particularly in regard to control of ß-cell mass, insulin and glucagon secretion. This will be measured relative to metabolic homeostasis and insulin sensitivity, so as to distinguish between direct acute effects of the CNS on islet cell function rather than peripheral metabolic effects to which islet cells act secondarily. Thus, the newly revealed `brain-to-islet map' will be validated as a functional guide, and novel mechanistic insight into CNS neuronal control of pancreatic islet cell functions gained. It is anticipated that this research will eventually translate into noel therapeutic approaches for the treatment of diabetes/obesity.

描述（由申请人提供）：与肥胖相关的 2 型糖尿病是全球范围内流行的主要健康问题，该疾病的发病特点是功能性胰岛 β 细胞群无法满足代谢需求，因此是一种严重的健康问题。胰岛素不足状态。因此，保护和保存足够的功能性 β 细胞量的方法具有治疗 2 型糖尿病的潜力。然而，人们对 β 细胞功能的营养和激素调节有很多了解。尽管 160 多年来人们就知道中枢神经系统 (CNS) 对胰岛功能具有显着的控制作用，但中枢神经系统对胰腺 ß 细胞的控制机制仍然模糊。在该提案中，其目的是利用胰岛。新型伪狂犬病病毒载体（PRV）作为逆行突触神经元示踪剂，可准确追踪体内胰岛和中枢神经系统特定区域之间的神经联系，这将通过几种体内顺行追踪技术来补充，以完善 PRV 逆行追踪。 Aim-1 将使用逆行和顺行神经跟踪方法来揭示小鼠中枢神经系统“大脑到胰岛的地形图”，这张图的分辨率为 5μm，并且是 3D 形式，将对其进行详细表征，特别是揭示神经细胞的类型。位于其中，并利用新颖的顺行跟踪技术来识别可以在该图谱中激活的特定神经元回路。在 Aim-2 中，“大脑到胰岛图谱”中的葡萄糖感应神经元将通过精确的立体定位传递进行操作。腺病毒载体类似地，在 Aim-3 中，将采用类似的立体定位方法，但专门针对特定的下丘脑胰岛素信号神经元，其中胰岛素受体和 IRS-2 基因功能将受到影响。然后，将评估中枢神经系统中与胰岛相连的区域中葡萄糖感应和/或胰岛素信号传导的改变是否会影响胰岛细胞功能。 ivo，特别是关于β细胞质量、胰岛素和胰高血糖素分泌的控制，这将相对于代谢稳态和胰岛素敏感性进行测量，以便区分中枢神经系统对胰岛细胞功能的直接急性影响而不是外周代谢影响。因此，新揭示的“脑到胰岛图”将被验证为功能指南，并获得对中枢神经系统神经控制胰岛细胞功能的新机制。预计这项研究最终将转化为治疗糖尿病/肥胖症的诺埃尔治疗方法。