A Novel Approach to Stroke Treatment: Acid-Sensing Iion Channel Inhibitors

治疗中风的新方法：酸敏感离子通道抑制剂

基本信息

批准号：
7616402
负责人：
ROGER Pancoast SIMON
金额：
$ 11.83万
依托单位：
VIROGENOMICS, INC.
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：
2009-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7616402
关键词：
ASIC channel Acidosis Acids Advanced Development Affect Amiloride Apoptotic Attention Brain Brain Injuries Calcium Cause of Death Cell Death Cell Death Process Cells Cerebral Ischemia Clinical Trials Data Effectiveness Excitatory Amino Acid Antagonists Family Glutamates Human Image In Vitro Infarction Injury Ion Channel Ischemia Ischemic Brain Injury Ischemic Stroke Knowledge Learning Mediating Memory Metabolic Modeling Molecular Necrosis Nervous System Physiology Neuraxis Neurons Neuroprotective Agents Neurotoxins Paper Permeability Play Process Publishing Research Rodent Model Role Stimulus Stroke Structure Synaptic plasticity System Tarantula Venoms Therapeutic Toxic effect United States Venoms acute stroke analog base brain cell disability editorial effective therapy in vitro Model in vivo inhibitor/antagonist member novel strategies perpetrators phrases prevent public health relevance response synthetic peptide

项目摘要

DESCRIPTION (provided by applicant): Stroke is the third leading cause of death and a leading cause of serious, long-term disability in the United States. Although in recent years enormous progress has been made towards defining the cellular and molecular responses of the brain to ischemia, our knowledge is not yet adequate to protect against ischemic injury. No neuroprotective agents of demonstrable efficacy have yet passed clinical trials. However, we do know that calcium entry is the central feature of ischemic brain injury. Blockade of calcium entry prevents brain cell death during stroke. In a search for other effectors of brain injury in the setting of ischemia, our attention has been drawn to the recently discovered family of acid-sensing ion channels (ASICs). As acidosis is a central and prominent metabolic feature of ischemic brain and as ASICs are capable of Ca2+ permeability we have hypothesized a pathological function of ASIC's in ischemic brain injury. Members of this ion channel family respond to acidic stimuli and would therefore be activated by that central feature of ischemia, acidosis and in that setting, would flux Ca2+. Our colleagues and we have offered recent data, to include Ca2+ imaging, showing that ASIC channels flux Ca2+ in native neurons in a pH dependent manner. We have shown that this Ca2+ flux is markedly potentiated by modeled ischemia and that this Ca2+ flux is glutamate independent. ASICs are expressed throughout the mammalian central nervous system where they function in synaptic plasticity, learning and memory. Their ubiquitous presence makes them potentially important modulators of brain injury in the setting of ischemia. The discovery of ASIC blockade is the first discovery in 20 years of a new, potent mechanism to prevent calcium toxicity in acute stroke. The aim of this proposal is to advance the development of inhibitors of ASIC channels towards the creation of an acute stroke therapeutic. PUBLIC HEALTH RELEVANCE: Stroke is the third leading cause of death and a leading cause of serious, long-term disability in the United States. Blockade of calcium entry prevents brain cell death during stroke. The discovery of ASIC blockade is the first discovery in 20 years of a new, potent mechanism to prevent calcium toxicity in acute stroke.

描述（由申请人提供）：中风是美国第三大死亡原因，也是导致严重、长期残疾的主要原因。尽管近年来在定义大脑对缺血的细胞和分子反应方面取得了巨大进展，但我们的知识还不足以预防缺血性损伤。目前还没有具有明显功效的神经保护剂通过临床试验。然而，我们确实知道钙进入是缺血性脑损伤的核心特征。阻断钙进入可防止中风期间脑细胞死亡。在寻找缺血情况下脑损伤的其他效应物时，我们的注意力被最近发现的酸敏感离子通道（ASIC）家族所吸引。由于酸中毒是缺血性脑的一个重要且显着的代谢特征，并且由于 ASIC 具有 Ca2+ 渗透性，因此我们假设 ASIC 在缺血性脑损伤中具有病理功能。该离子通道家族的成员对酸性刺激有反应，因此会被缺血、酸中毒的中心特征激活，在这种情况下，会流动 Ca2+。我们的同事和我们提供了最新的数据，包括 Ca2+ 成像，表明 ASIC 以 pH 依赖的方式在天然神经元中通道流动 Ca2+。我们已经证明，这种 Ca2+ 通量通过模拟缺血显着增强，并且这种 Ca2+ 通量不依赖于谷氨酸。 ASIC 在整个哺乳动物中枢神经系统中表达，它们在突触可塑性、学习和记忆中发挥作用。它们的普遍存在使它们成为缺血情况下脑损伤的潜在重要调节剂。 ASIC 阻断的发现是 20 年来首次发现一种新的、有效的机制，可以预防急性中风中的钙中毒。该提案的目的是推进 ASIC 通道抑制剂的开发，以创建急性中风治疗药物。公共卫生相关性：中风是美国第三大死亡原因，也是导致严重、长期残疾的主要原因。阻断钙进入可防止中风期间脑细胞死亡。 ASIC 阻断的发现是 20 年来首次发现一种新的、有效的机制，可以预防急性中风中的钙中毒。