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Central Control of Pancreatic Islet Function

胰岛功能的中央控制

基本信息

批准号：
9096773
负责人：
Christopher J Rhodes
金额：
$ 46.73万
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/9096773
关键词：
Acute Address Adenovirus Vector Affect Alpha Cell Biochemical Brain Brain region Cell physiology Cells Characteristics Communication Complement Complex Data Diabetes Mellitus Elements Endocrine 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 Nervous System control Neuraxis Neurologic Neurons Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Onset of illness Pancreas Peripheral Physiological Pseudorabies Regulation Research Resolution Rodent Signal Transduction Techniques Technology Therapeutic Tracer Transgenic Mice Translating Viral Vector adenoviral-mediated base gene function hormone regulation in vivo insight insulin secretion insulin sensitivity insulin signaling islet meetings neglect nerve supply neuronal circuitry novel novel therapeutic intervention pancreatic islet function reduce symptoms research study

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(申请人提供)：肥胖相关的2型糖尿病是一个世界性流行的主要健康问题。该病的发病特点是功能性胰岛细胞群不能满足代谢需求，因此是胰岛素不足的状态。因此，一种保护和保存足够的功能性？细胞团的方法对2型糖尿病具有治疗潜力。很多人都知道营养和荷尔蒙对？细胞功能的调节。然而，尽管人们早在160多年前就知道中枢神经系统(CNS)对胰岛功能有很大程度的控制，但CNS对胰岛细胞的控制机制仍然不清楚。事实上，连接胰岛的中枢神经系统的确切区域是未知的。在本提案中，它打算使用一个新型伪狂犬病病毒载体(PRV)作为逆行跨突触神经示踪剂，可在体内准确追踪胰岛和中枢神经系统特定区域之间的神经元联系。这将与几种体内顺行示踪技术相补充，以完善PRV逆行示踪。AIM-1将同时使用逆行和顺行神经元追踪方法，以5微米的分辨率和3D显示小鼠的中枢神经系统“脑-胰岛地形图”。这张图将被详细描述，特别是为了揭示什么样的神经细胞并利用新的顺行追踪技术来识别可以在该图中激活的特定神经元回路。在AIM-2中，将使用腺病毒载体的精确立体定位递送来操纵脑-胰岛映射中的葡萄糖感受神经元这会改变下丘脑特定亚区的葡萄糖激活酶活性。同样，在AIM-3中，将采取类似的立体定位方法，但目标是特定的下丘脑胰岛素信号神经元，在那里胰岛素受体和IRS-2基因的功能将受到操纵。然后，将评估中枢神经系统与胰岛连接的区域的葡萄糖感知和/或胰岛素信号的变化是否会影响体内胰岛细胞的功能，特别是在控制？细胞质量、胰岛素和胰高血糖素分泌方面。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，而不是胰岛细胞对其辅助作用的外周代谢影响。因此，新发现的“脑-胰岛图”将被证实为一种功能指南，并获得了对中枢神经系统神经元控制胰岛细胞功能的新的机制见解。预计这项研究最终将转化为治疗糖尿病/肥胖症的新的治疗方法。