Adrenergic transmission properties and implication

肾上腺素能传输特性及意义

• 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
• 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' 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

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， 例如大脑中的感觉处理、睡眠-觉醒/唤醒状态转换和注意力等 在各种组织和器官中的生物过程，包括心脏、胰腺和脾脏。 肾上腺素能传递的失调与许多神经系统疾病有关，包括 老年痴呆症、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可能参与多种生理和病理状况， 肾上腺素能传递精确调节和确切的功能作用仍然不清楚， 主要是由于用于监测NE/Epi的可用工具的局限性。我们最近开发了一个家庭 基于强度的G蛋白偶联受体（GPCR）激活的遗传编码NE 通过将环状排列的绿色荧光蛋白（cpGFP）与人荧光蛋白偶联， 肾上腺素能受体虽然这些GRABNE传感器允许第一次可视化肾上腺素能 传输，传感器在确定肾上腺素能神经元的突触特性方面是次优的。 传输为了促进NE/Epi研究，我们最近设计了高性能GRABNE 能够高灵敏度和高分辨率可视化肾上腺素能传递事件的传感器 在单个释放点。新传感器和初步数据增强了我们测试的信心 假设高性能GRABNE传感器可以解决肾上腺素能传递 可以推断肾上腺素能功能作用的性质。该应用程序遵循两个具体的 目的：目的1是确定高性能GRABNE传感器是否可以解决肾上腺素能 目的2是测试肾上腺素能传递是否在肾上腺素能传递中起重要作用。 要求精确和注意力的行为。我们希望拟议的实验， 描述一种新形式的神经元传递的第一组基本突触特性， 定义了一个新的，独特的功能作用肾上腺素能传输。