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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：
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.