Mechanism and function of transient adenosine signaling in the brain

大脑中瞬时腺苷信号传导的机制和功能

• 批准号: 8387636
• 负责人: B. JILL VENTON
• 金额: $ 30.94万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8387636
• 关键词: Adenosine; Astrocytes; Blood Vessels; Blood flow; Brain; Brain region; Cerebrovascular Circulation; Couples; Disease; Dopamine; Drug Delivery Systems; Drug abuse; Electric Stimulation; Energy Supply; Frequencies; Glutamates; Goals; Green Fluorescent Proteins; Huntington Disease; Ischemia; Knowledge; Label; Lead; Long-Term Effects; Long-Term Potentiation; Measures; Mental Depression; Methods; Microelectrodes; Mission; Monitor; Nature; Neuromodulator; Neuronal Plasticity; Neurons; Neurotransmitters; Organism; Outcome; Oxygen; Pain; Parkinson Disease; Pharmaceutical Preparations; Process; Public Health; Purinergic P1 Receptors; Rattus; Regulation; Research; Resolution; Signal Transduction; Slice; Source; Stimulus; System; Technology; Testing; Therapeutic; Thinking; Time; addiction; adenosine receptor activation; base; burden of illness; extracellular; in vivo; innovation; insight; instrumentation; nervous system disorder; neuroregulation; neurotransmission; novel; receptor; receptor function; research study; response; sensor; treatment strategy

DESCRIPTION (provided by applicant): Adenosine is a neuromodulator that regulates neurotransmission and cerebral blood flow but the nature of adenosine signaling in the brain is not well characterized. Most studies have described long-term effects of activation of adenosine receptors or changes in adenosine basal levels. Recently, rapid changes in adenosine have recently been discovered but the function of these transient changes is not known. The long-term goal of this lab is to develop new microelectrode methods to understand the rapid dynamics of neuromodulation in the brain. The objective of this project is to investigate the formation and function of transient adenosine signaling. This research is innovative because it challenges the paradigm that neuromodulation by adenosine is slow and advances technology by employing novel electrochemical sensors that overcome critical instrumentation barriers of slow temporal resolution and low sensitivity. The central hypothesis is that transient adenosine release occurs throughout the brain, is regulated by adenosine receptors, and functions to modulate neurotransmission and blood flow on a rapid time scale. This hypothesis will be tested with three Aims. In Aim 1, electrically-stimulated adenosine release will be characterized in multiple brain regions. Pharmacological experiments will be performed in brain slices to test the mechanism of adenosine formation and the cellular sources in each region. In Aim 2, spontaneous adenosine transients will be studied in anesthetized rats. These transients occur without drugs but are more frequent after administration of an A1 receptor antagonist. This study will provide a better understanding of how adenosine receptors regulate transient adenosine release. The goal of Aim 3 is to determine the function of transient adenosine release. The two hypotheses are that adenosine modulates neurotransmission and blood flow. The effect of exogenously applied adenosine on dopamine neurotransmission will be tested in brain slices. In addition, the effect of transient adenosine release on blood flow will be studied n vivo. This research will result in a better understanding of the formation and function of transien adenosine release. Adenosine based therapeutics have been proposed as possible treatments for neurological diseases such as pain, Parkinson disease, Huntington's disease, and drug abuse. New insight into the time course of neuromodulation could lead to better manipulation of transient adenosine changes to mitigate diseases caused by impaired neurotransmission. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because the characterization of the formation and function of adenosine signaling in the brain is ultimately expected to lead to a better understanding of how drugs that act on the adenosine system can be used to treat diseases that result from impaired neurotransmission. Thus, the proposed research is relevant to the NIH's mission to develop fundamental knowledge about the nature of living systems that can be applied to reduce the burdens of illness.

描述（由申请人提供）：腺苷是一种调节神经传递和脑血流的神经调节剂，但大脑中腺苷信号传导的性质尚未得到很好的表征。大多数研究描述了腺苷受体激活或腺苷基础水平变化的长期影响。最近，人们发现了腺苷的快速变化，但这些瞬时变化的功能尚不清楚。该实验室的长期目标是开发新的微电极方法来了解大脑神经调节的快速动态。该项目的目的是研究瞬时腺苷信号传导的形成和功能。这项研究具有创新性，因为它挑战了腺苷神经调节缓慢的范式，并通过采用新型电化学传感器来克服慢时间分辨率和低灵敏度的关键仪器障碍，从而推进了技术发展。中心假设是短暂的腺苷释放发生在整个大脑中，受到腺苷受体的调节，并在快速时间尺度上调节神经传递和血流。该假设将通过三个目标进行检验。在目标 1 中，电刺激腺苷释放将在多个大脑区域进行表征。将在脑切片中进行药理学实验，以测试腺苷形成的机制和每个区域的细胞来源。在目标 2 中，将在麻醉大鼠中研究自发腺苷瞬变。这些瞬变现象在没有药物的情况下也会发生，但在使用 A1 受体拮抗剂后会更加频繁。这项研究将有助于更好地了解腺苷受体如何调节短暂的腺苷释放。目标 3 的目标是确定瞬时腺苷释放的功能。这两个假设是腺苷调节神经传递和血流。将在脑切片中测试外源应用的腺苷对多巴胺神经传递的影响。此外，还将在体内研究瞬时腺苷释放对血流的影响。这项研究将有助于更好地了解瞬时腺苷释放的形成和功能。基于腺苷的疗法已被提议作为神经系统疾病（例如疼痛、帕金森病、亨廷顿病和药物滥用）的可能治疗方法。对神经调节时间过程的新见解可能会导致更好地操纵短暂的腺苷变化，以减轻神经传递受损引起的疾病。 公共健康相关性：拟议的研究与公共健康相关，因为大脑中腺苷信号传导的形成和功能的表征最终有望使人们更好地了解作用于腺苷系统的药物如何用于治疗神经传递受损引起的疾病。因此，拟议的研究与美国国立卫生研究院的使命相关，即开发有关生命系统本质的基础知识，这些知识可用于减轻疾病负担。