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Acid-sensing channels as novel target for brain ischemia

酸感应通道作为脑缺血的新靶点

基本信息

批准号：
7215531
负责人：
ZHIGANG XIONG
金额：
$ 33.99万
依托单位：
LEGACY EMANUEL HOSPITAL AND HEALTH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2008-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7215531
关键词：
ASIC channel Acidosis Acids Acute Amiloride Animals Brain Brain Hypoxia-Ischemia Brain Injuries Brain Ischemia COS-7 Cell Cell Line Cells Chemical Models Chemosensitization Class Condition Data Dose Drops Genes Glucose Glutamate Receptor Glutamates Hour Hypoxia Image In Vitro Infarction Injury Intraventricular Injections Ions Iowa Ischemia Ischemic Brain Injury Ischemic Neuronal Injury Knock-out Knockout Mice Laboratories Laboratory Research Mails Mediating Metabolic Modeling Molecular Mus N-Methyl-D-Aspartate Receptors Neuraxis Neuronal Injury Neurons Neuroprotective Agents Numbers Oxygen Pathology Pathway interactions Permeability Pharmacology Pisum sativum Play Property Protein Kinase Inhibitors Protocols documentation Rain Rattus Relative (related person)Resistance Role Slice Solutions Standards of Weights and Measures Statistically Significant Testing Time Universities Xenopus oocyte brain volume cell injury deprivation desensitization epithelial Na+ channel extracellular in vitro Model in vivo in vivo Model ion channel blocker knockout gene member nervous system disorder neurotoxicity novel patch clamp protein kinase inhibitor receptor research study response stable cell line trend voltage voltage clamp

项目摘要

DESCRIPTION (provided by applicant): Brain acidosis is a common feature in acute neurological diseases particularly in ischemia, and has been assumed to play an important role in the pathology of neuronal injury. However, the cellular and molecular mechanisms underlying acidosis-induced injury remain uncertain, multifactorial and vague. We have substantial preliminary data demonstrating that activation of newly described acid-sensing ion channels (ASICs), members of Degenerin/EnaC superfamily, and subsequent Ca2+ entry through these channels are largely responsible for acidosis-induced, glutamate receptor-independent neuronal injury. In cultured mouse cortical neurons, lowering pH activates amiloride-sensitive ASIC currents. In the majority of these neurons, ASICs are also permeable to Ca2+, and activation of these channels induces increases in the concentration of intracellular Ca2+([Ca2+]i). Activation of ASICs by brief incubation of neurons with acidic solutions induces time-dependent cell injury in the presence of the blockers for both voltage-gated Ca2+ channels and the glutamate receptors. This acid-induced injury is, however, inhibited by the blockers of ASICs, and by reducing the extracellular [Ca2+]. Acid treatment of COS-7 cells that lack functional ASICs does not induce significant cell injury. Similar to the primary cultured neurons, acid treatment induces injury in organotypic brain slices, and the injury of brain slices is inhibited by the blockers of ASICs. Preliminary in vivo studies also demonstrate that intraventricular injection of ASIC1 blocker reduced the infarction volume, and knockout of the ASIC1 gene protects the mouse brain from ischemic injury. Furthermore, our preliminary studies demonstrate that ischemic treatment and metabolic inhibition dramatically potentiate the ASIC currents. This potentiation of ASICs in turn increases acidosis-induced neuronal injury. Our overall objective is to investigate the pathological role of ASICs in the central nervous system and to test the hypothesis that activation of ASICs with subsequent Ca2+ entry is largely responsible for acidosis-mediated, glutamate-independent ischemic brain injury. Specific Aims Aim 1. Ca2+ -permeability of acid-sensing ion channels in CNS neurons Aim 2. Specific subunit configurations are responsible for acidosis-induced neuronal injury Aim 3. Potentiation of ASIC currents by hypoxia/ischemia Aim 4. Neuroprotective role of ASIC blockers or ASIC gene knockout in an in vivo model of brain ischemia and the organotypic brain slices

描述（由申请人提供）：脑酸中毒是急性神经系统疾病（尤其是缺血）的常见特征，并且被认为在神经元损伤的病理学中发挥重要作用。然而，酸中毒引起的损伤的细胞和分子机制仍然不确定、多因素且模糊。我们有大量初步数据表明，新描述的酸敏感离子通道 (ASIC)（Degenerin/EnaC 超家族成员）的激活以及随后通过这些通道的 Ca2+ 进入在很大程度上负责酸中毒诱导的、不依赖于谷氨酸受体的神经元损伤。在培养的小鼠皮质神经元中，降低 pH 值会激活阿米洛利敏感的 ASIC 电流。在大多数这些神经元中，ASIC 也可渗透 Ca2+，这些通道的激活会导致细胞内 Ca2+([Ca2+]i) 浓度增加。在存在电压门控 Ca2+ 通道和谷氨酸受体阻断剂的情况下，通过用酸性溶液短暂孵育神经元来激活 ASIC，会诱导时间依赖性细胞损伤。然而，这种酸诱导的损伤可通过 ASIC 阻滞剂和减少细胞外 [Ca2+] 来抑制。对缺乏功能性 ASIC 的 COS-7 细胞进行酸处理不会引起明显的细胞损伤。与原代培养的神经元类似，酸处理会引起器官型脑切片的损伤，并且脑切片的损伤被 ASIC 的阻断剂抑制。初步体内研究还表明，脑室内注射 ASIC1 阻滞剂可减少梗塞体积，敲除 ASIC1 基因可保护小鼠大脑免受缺血性损伤。此外，我们的初步研究表明，缺血治疗和代谢抑制可显着增强 ASIC 电流。 ASIC 的这种增强反过来又增加了酸中毒引起的神经元损伤。我们的总体目标是研究 ASIC 在中枢神经系统中的病理作用，并检验以下假设：ASIC 的激活以及随后的 Ca2+ 进入在很大程度上导致了酸中毒介导的、不依赖于谷氨酸的缺血性脑损伤。具体目标目标 1. CNS 神经元酸敏感离子通道的 Ca2+ 通透性目标 2. 特定的亚基构型是酸中毒引起的神经元损伤的原因目标 3. 缺氧/缺血导致 ASIC 电流增强目标 4. ASIC 阻滞剂或 ASIC 基因敲除在脑缺血体内模型和器官型脑切片中的神经保护作用