Adrenergic transmission properties and implication

肾上腺素能传输特性及意义

基本信息

批准号：
10637114
负责人：
Mark Beenhakker
金额：
$ 40.38万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10637114
关键词：
Adrenergic Agents Adrenergic Receptor Algorithmic Analysis Alzheimer&apos s Disease Arousal Attention Attentional deficit Behavior Biological Process Brain Cardiovascular Diseases Cell Nucleus Central Nervous System Clinical Cognition Complex Coupling Data Depressive disorder Diffusion Engineering Epinephrine Event Family Future G-Protein-Coupled Receptors Gold Green Fluorescent Proteins Health Heart Human Image Analysis Immune Individual Investigation Link Mental disorders Microscopic Monitor Mus Neurons Neurotransmitters Norepinephrine Organ Output Pancreas Parkinson Disease Pathologic Performance Peripheral Peripheral Nervous System Physiological Physiological Processes Play Pontine structure Preparation Probability Property Receptor Activation Regulation Research Resolution Role Scheme Schizophrenia Sensory Signal Transduction Site Sleep Sleep Disorders Spleen Synapses Testing Tissues Visualization Wood material autism spectrum disorder cognitive function experimental study improved locus ceruleus structure monoamine nervous system disorder neurotransmission novel sensor tool transmission process tumorigenesis ultra high resolution

项目摘要

PROJECT SUMMARY Norepinephrine (NE) and epinephrine (Epi) have been implicated in complex cognitive functions, such as sensory processing, sleep-wake/arousal state transition and attention, in the brain, and other biological processes in various tissues and organs, including the heart, pancreas and spleen. Dysregulation of adrenergic transmission is linked to a number of neurological diseases, including Alzheimer’s disease, depressive disorders and schizophrenia, as well as many other health problems, including cardiovascular diseases, immune-deficiency and tumorigenesis. Despite the potential involvement of NE/Epi in myriad physiological and pathological conditions, the precise regulation and exact functional role of adrenergic transmission remain poorly defined, due primarily to limitations of available tools for monitoring NE/Epi. We have recently developed a family of intensity-based G-protein-coupled receptor (GPCR) activation-based genetically encoded NE (GRABNE) sensors by coupling a circular permutated green fluorescent protein (cpGFP) with a human adrenergic receptor. While these GRABNE sensors allowed the first visualization of adrenergic transmission, the sensors were suboptimal in determining synaptic properties of adrenergic transmission. To facilitate NE/Epi research, we recently engineered high-performance GRABNE sensors that allowed high-sensitivity and high-resolution visualization of adrenergic transmission events at single release sites. The new sensors and preliminary data build up our confidence to test the hypothesis that high-performance GRABNE sensors may resolve the adrenergic transmission properties that could deduce the adrenergic functional role. This application follows two specific aims: Aim 1 is to determine whether high-performance GRABNE sensors may resolve adrenergic transmission properties, and Aim 2 is to test whether adrenergic transmission plays an essential role in the precision- and attention-demanding behaviors. We expect the proposed experiments to characterize the first set of fundamental synaptic properties of a new form of neuronal transmission and define a novel, unique functional role for adrenergic transmission.

项目摘要去甲肾上腺素（NE）和肾上腺素（EPI）与复杂的认知功能有关，例如，在大脑和其他各种组织和器官的生物过程，包括心脏，胰腺和脾脏。肾上腺素传播的失调与许多神经疾病有关，包括阿尔茨海默氏病，抑郁症和精神分裂症以及许多其他健康问题，包括心血管疾病，免疫缺陷和肿瘤发生。尽管NE/EPI潜在参与了无数生理和病理状况，但肾上腺素传播的确切调节和确切的功能作用仍然很差，应得主要是用于监视NE/EPI的可用工具。基于强度的G蛋白偶联受体（GPCR）激活的基因编码NE （grabne）传感器通过将圆形排列的绿色荧光蛋白（CPGFP）耦合肾上腺素受体。传输，传感器在确定肾上腺素能的突触特性方面是次优的传输。传感器允许高敏性和高分辨率可视化adreneergic传播事件事件事件在单个释放站点中。假设高性能Grabne传感器可以解决肾上腺素能的传播可以干扰肾上腺素功能的特性。目的：目标1是确定高性能Grabne传感器是否可以解决Adreneermo 传输属性和目标2是测试肾上腺素能传播是否在精确和指标的行为。表征新形式的神经元传播形式的第一组基本突触特性和为腺能传播定义了新颖的，独特的功能作用。