Adenosine receptor activation in spreading depolarization and ischemic injury

腺苷受体激活在扩散去极化和缺血性损伤中的作用

基本信息

批准号：
8311301
负责人：
Britta Lindquist
金额：
$ 3.4万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8311301
关键词：
Adenosine Adenosine A2A Receptor Adult Affect Animal Model Area Basic Science Blood Vessels Blood flow Brain Brain Injuries Brain region Caliber Cause of Death Cell surface Cerebrum Cessation of life Clinical Sciences Complement Coupling Distal Drops Electrophysiology (science)Event Experimental Designs Failure Fellowship G-Protein-Coupled Receptors Goals Hippocampus (Brain)Homeostasis Hour Human Hyperemia Image In Vitro Incidence Infarction Injury Intravenous Ischemia Ischemic Brain Injury Ischemic Penumbra Ischemic Stroke Knowledge Lasers Lead Link Literature Mediating Mediator of activation protein Mental Depression Metabolic Methodology Methods Middle Cerebral Artery Occlusion Modeling Monitor Mus Neurologic Neurons Normal tissue morphology Optics Outcome Pathology Patients Physicians Purinergic P1 Receptors Reaction Recovery Recruitment Activity Research Role Science Scientist Signal Transduction Slice Stroke Synapses Synaptic Potentials Synaptic Transmission Techniques Testing Theft Time Tissues Training Translational Research United States Vasodilation Work adenosine receptor activation base brain electrical activity brain tissue cost design hemodynamics in vivo injured ischemic lesion mouse model nervous system disorder neuron loss novel post stroke pre-doctoral prevent receptor research study response skills spreading depression stroke therapy therapy development thrombolysis

项目摘要

DESCRIPTION (provided by applicant): The overall research goal of this fellowship proposal is to evaluate the involvement of adenosine receptors in brain injury resulting from ischemic stroke. Repetitive spreading depolarization (SD) events occur spontaneously after ischemic stroke, and contribute to the expansion of injury. SD is a wave of massive cellular depolarization which disturbs ionic homeostasis and depletes energy in the brain. In healthy tissue, SD is followed by an interval of reduced electrical activity and increased blood flow, whereas in injured tissue with minimal electrical activity, SD is followed by decreased blood flow and neuronal cell death. Mechanisms underlying these phenomena are not well understood. Both neuronal and vascular reactions to SD might be explained by adenosine receptor activation. Adenosine, a low-energy metabolite of ATP, accumulates during periods of metabolic imbalance. By activating G-protein coupled receptors on the surface of cells, adenosine can contribute to neuronal silence (via the A1 receptor) and vasodilation (via the A2A receptor). Adenosine A2A receptors are implicated in post-ischemic brain damage in animal models of stroke, but the mechanism is yet unknown and might be related to SD. In this proposal, experiments are designed to determine the role of adenosine receptor activation in recovery from spreading depolarization events in normal tissue and in a stroke model. Aim 1 will evaluate the activation of adenosine A1 and A2A receptors after SD in otherwise normal brain tissue from mice, using in vitro and in vivo methods to parse out neuronal and vascular effects. Aim 2 will use an in vivo mouse model of ischemic stroke to examine mechanisms by which adenosine receptors may persistently reduce neuronal activity and explain the paradoxical drop in blood flow in vulnerable areas. Major methodologies to be utilized include brain slice electrophysiology, in vivo electrophysiology, intrinsic optical signals, laser speckle contrast imaging, and histological assessment of ischemic lesions. These studies will contribute to the fellow's predoctoral training in neurological disease. The results of the proposed experiments will elucidate mechanisms of recovery and injury in the brain after stroke, and may suggest novel treatments to prevent the delayed expansion of ischemic injury.

描述（由申请人提供）：该奖学金提案的总体研究目标是评估腺苷受体在缺血性中风引起的脑损伤中的作用。缺血性中风后自发发生重复性扩散去极化（SD）事件，并导致损伤扩大。 SD 是一种大规模的细胞去极化波，它会扰乱离子稳态并消耗大脑中的能量。在健康组织中，SD之后是电活动减少和血流量增加的时间间隔，而在电活动最小的受损组织中，SD之后是血流量减少和神经元细胞死亡。这些现象背后的机制尚不清楚。 SD 的神经元和血管反应都可以通过腺苷受体激活来解释。腺苷是 ATP 的一种低能代谢物，在代谢失衡期间会积累。通过激活细胞表面的 G 蛋白偶联受体，腺苷可以促进神经元沉默（通过 A1 受体）和血管舒张（通过 A2A 受体）。腺苷A2A受体与中风动物模型的缺血后脑损伤有关，但其机制尚不清楚，可能与SD有关。在该提案中，实验旨在确定腺苷受体激活在正常组织和中风模型中从扩散去极化事件恢复中的作用。目标 1 将评估 SD 后小鼠正常脑组织中腺苷 A1 和 A2A 受体的激活情况，使用体外和体内方法解析神经元和血管效应。目标 2 将使用缺血性中风的体内小鼠模型来检查腺苷受体可能持续减少神经元活动的机制，并解释脆弱区域血流量的矛盾下降。使用的主要方法包括脑切片电生理学、体内电生理学、内在光信号、激光散斑对比成像和缺血性病变的组织学评估。这些研究将有助于该研究员在神经系统疾病方面的博士前培训。所提出的实验结果将阐明中风后大脑的恢复和损伤机制，并可能提出新的治疗方法来防止缺血性损伤的延迟扩展。