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

• 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
• 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; 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

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，是美国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已取得了巨大进展，但我们的知识尚不足以防止缺血性损伤。尚未通过临床试验的可证明功效的神经保护剂。但是，我们确实知道钙进入是缺血性脑损伤的主要特征。钙进入的封锁阻止了中风期间的脑细胞死亡。在寻找缺血的其他脑损伤效应因素时，我们的注意力已引起最近发现的酸性离子通道（ASIC）的家族。由于酸中毒是缺血性大脑的中心代谢特征，并且由于ASIC具有Ca2+渗透性，因此我们假设ASIC在缺血性脑损伤中的病理功能。该离子通道家族的成员对酸性刺激有反应，因此将被缺血，酸中毒和在这种情况下的中心特征所激活。我们的同事和我们提供了最近的数据，包括Ca2+成像，表明ASIC通道以pH为依赖性的方式中的天然神经元中的通量Ca2+。我们已经表明，这种Ca2+通量被建模的缺血显着增强，并且该Ca2+通量独立于谷氨酸。 ASIC在整个哺乳动物中枢神经系统中都表达，它们在突触可塑性，学习和记忆中发挥作用。它们无处不在的存在使它们在缺血的情况下可能是脑损伤的潜在重要调节剂。 ASIC封锁的发现是20年来的第一个发现，可以防止急性中风的钙毒性。该提议的目的是将ASIC渠道抑制剂的发展发展为创建急性中风治疗。公共卫生相关性：中风是美国的第三大主要原因，也是美国长期残疾的主要原因。钙进入的封锁阻止了中风期间的脑细胞死亡。 ASIC封锁的发现是20年来的第一个发现，可以防止急性中风的钙毒性。