A new strategy for protection from cerebral ischemia

预防脑缺血的新策略

基本信息

批准号：
7762239
负责人：
YING XIA
金额：
$ 8.71万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-01 至 2010-05-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7762239
关键词：
Acupuncture procedure Attention Attenuated Award Blood flow Brain Brain Infarction Brain Injuries Cell Membrane Proteins Cerebral Ischemia Cerebrovascular Circulation Cerebrum Cessation of life Complementary and alternative medicine Data Early treatment Employee Strikes Event Family Funding Grant Home environment Homeostasis Hospitals Hypoxia Individual Inflammatory Inflammatory Response Injury Investigation Ischemia Ischemic Brain Injury Knowledge Lead Light Mediating Middle Cerebral Artery Occlusion Modality Molecular National Center for Complementary and Alternative Medicine Needles Neurologic Neurons Opioid Opioid Receptor Outcome Patients Play Prevention Production Receptor Activation Receptor Down-Regulation Receptor Inhibition Receptor Up-Regulation Recovery Regulation Research Risk Role Science Scientist Signal Transduction Simulate Solutions Somatosensory Evoked Potentials Stroke Study Section System Techniques Testing Therapeutic Transgenic Model Transgenic Organisms Travel United States United States National Institutes of Health Up-Regulation Work acute stroke attenuation base cost cytokine delta opioid receptor design disability effective therapy experience neuron apoptosis novel novel strategies novel therapeutics prevent public health relevance receptor expression

项目摘要

DESCRIPTION (provided by applicant): Ischemic brain injury such as stroke is a leading cause of neurological disability and death in the States. There is, however, no effective strategy to protect the brain from ischemic injury. Recently, we have made exciting observations on effect of electro-acupuncture (EA) on cerebral ischemia. The most striking finding is that EA remarkably reduces brain infarction due to the occlusion of middle cerebral artery, which is dependent on the EA-triggered cellular/molecular events in the brain. Since our studies and those of others have shown that 1) activation of delta-opioid receptor (DOR) attenuates hypoxic/ischemic disruption of ionic homeostasis that triggers neuronal apoptosis and death; 2) DOR up-regulation enhances intracellular survival signals; 3) opioid receptor activation inhibits inflammatory responses, e.g., production of inflammatory cytokines that plays a critical role in ischemic injury; and 4) DOR inhibition largely attenuates the EA-induced protection against ischemic injury, it is likely that the EA-induced protection represents the outcome of cellular and molecular regulation at multiple levels in the brain. Specifically, it may depend on DOR up-regulation and the DOR-mediated stabilization of ionic homeostasis and modulation of survival/death signals. The general hypothesis of this proposal is that EA protects against cerebral ischemia mainly through DOR up-regulation and the DOR-mediated modulation of cellular and molecular signaling in neurons.. With molecular, transgenic and electrophysiological approaches, this proposal is designed to accomplish 3 specific aims: 1) to investigate if EA protects the brain from cerebral ischemia via DOR up-regulation; 2) to investigate if the EA protection is mediated by DOR-based stabilization of ionic homeostasis; and 3) to investigate if the EA protection relies on DOR-mediated inhibition of inflammatory responses to ischemia. The outcome data of this project may yield important information on the mechanism underlying the EA-induced protection from cerebral ischemia and may provide novel clues for therapeutic solutions of stroke. PUBLIC HEALTH RELEVANCE: Stroke is a leading cause of neurological disability and death in the United States. However, there is no effective therapy to date to protect the brain from stroke-induced brain injury. To seek novel approaches to prevent/treat stroke, we have recently made exciting observations on the effect of electro- acupuncture (EA) on stroke-induced injury. The most striking and surprising finding is that EA, through little needles without any other treatment, remarkably reduces stroke-induced brain injury via the regulation of delta-opioid receptor (a cell membrane protein). Also, functional studies showed that EA promotes the recovery of brain function after stroke. Our finding thus suggests important therapeutic potential for EA in stroke. In this application, we propose to use modern techniques including molecular, transgenic and electrophysiological approaches to test three specific hypotheses for exploring mechanisms underlying the EA protection against stroke. Our preliminary studies have shown that this proposal is feasible and will very likely yield important information on the EA-induced protection and eventually shed light on new therapeutic modalities of stroke.

描述（由申请人提供）：缺血性脑损伤（例如中风）是美国神经残疾和死亡的主要原因。然而，没有有效的策略来保护大脑免受缺血性损伤。最近，我们对电针（EA）对脑缺血的影响取得了令人兴奋的观察结果。最引人注目的发现是，电针可显着减少由于大脑中动脉闭塞而导致的脑梗死，这取决于电针触发的大脑细胞/分子事件。因为我们和其他人的研究表明：1）δ-阿片受体（DOR）的激活可以减轻离子稳态的缺氧/缺血性破坏，从而引发神经元凋亡和死亡； 2）DOR上调增强细胞内生存信号； 3)阿片受体激活抑制炎症反应，例如在缺血性损伤中起关键作用的炎症细胞因子的产生； 4) DOR抑制在很大程度上减弱了EA诱导的针对缺血性损伤的保护作用，EA诱导的保护作用很可能代表了大脑中多个水平的细胞和分子调节的结果。具体来说，它可能取决于 DOR 的上调以及 DOR 介导的离子稳态稳定和生存/死亡信号的调节。该提案的总体假设是，EA 主要通过 DOR 上调以及 DOR 介导的神经元细胞和分子信号传导调节来预防脑缺血。通过分子、转基因和电生理学方法，该提案旨在实现 3 个具体目标目的：1) 研究 EA 是否通过上调 DOR 来保护大脑免受脑缺血； 2) 研究 EA 保护是否是由基于 DOR 的离子稳态稳定介导的； 3) 研究 EA 保护是否依赖于 DOR 介导的对缺血炎症反应的抑制。该项目的结果数据可能会提供关于电针诱导的脑缺血保护机制的重要信息，并可能为中风的治疗方案提供新的线索。公共卫生相关性：中风是美国神经残疾和死亡的主要原因。然而，迄今为止还没有有效的治疗方法可以保护大脑免受中风引起的脑损伤。为了寻求预防/治疗中风的新方法，我们最近对电针（EA）对中风引起的损伤的影响进行了令人兴奋的观察。最引人注目和令人惊讶的发现是，电针通过小针，无需任何其他治疗，通过调节 δ-阿片受体（一种细胞膜蛋白），显着减少中风引起的脑损伤。此外，功能研究表明，电针可以促进中风后大脑功能的恢复。因此，我们的发现表明 EA 在中风中具有重要的治疗潜力。在此应用中，我们建议使用包括分子、转基因和电生理学方法在内的现代技术来测试三个具体假设，以探索 EA 预防中风的潜在机制。我们的初步研究表明，该提议是可行的，并且很可能会产生关于电针诱导的保护的重要信息，并最终揭示中风的新治疗方式。