The role of Na+/H+ exchanger in cerebral ischemia

Na/H交换体在脑缺血中的作用

• 批准号: 8256768
• 负责人: Dandan Sun
• 金额: $ 34.15万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-04 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8256768
• 关键词: Ablation; Acute; Adverse effects; Animal Experiments; Applications Grants; Astrocytes; Attenuated; Brain; Carrier Proteins; Cells; Cerebral Ischemia; Cerebrum; Cessation of life; Coronary Artery Bypass; Dendrites; Event; Experimental Animal Model; Funding; Generations; Genetic; Glucose; Goals; Homeostasis; In Vitro; Inflammatory Response; Injury; Ion Transport; Ions; Ischemia; Ischemic Brain Injury; Ischemic-Hypoxic Encephalopathy; Knowledge; MAP Kinase Gene; MAPK14 gene; Mediating; Membrane Potentials; Microglia; Mitochondria; Modeling; Myocardial Ischemia; Myocardial Reperfusion; NADPH Oxidase; NF-kappa B; Neuronal Injury; Neurons; Oxygen; Patients; Phase; Phosphorylation; Play; Protein Isoforms; Regulation; Reperfusion Injury; Research; Respiratory Burst; Role; Staging; Stroke; Testing; Therapeutic Agents; Time; cariporide; chloride-cotransporter potassium; deprivation; effective therapy; in vivo; inhibitor/antagonist; meetings; mitochondrial dysfunction; mitochondrial membrane; neuronal cell body; neuroprotection; postsynaptic; preclinical study; response; sodium-hydrogen exchanger 2

This is a revised competitive renewal grant application (R01NS48216-A1) to study the role of Na+/H+ exchanger isoform 1 (NHE1) in focal ischemic damage. Limited information is known about the role of NHE-1 in cerebral ischemia and whether inhibition of NHE-1 is neuroprotective against ischemic brain damage. In the initial funding period, we found that NHE-1 was essential in regulation of somata pHi in cortical astrocytes and neurons. NHE-1 activity in astrocytes and neurons was stimulated during reoxygenation (REOX) following oxygen and glucose deprivation (OGD). Either pharmacological inhibition or genetic ablation of NHE-1 activity protected cells from ischemic damage in in vitro and in vivo ischemic models. Excessive stimulation of NHE-1 activity led to dysregulation of intracellular Na+ and Ca2+ homeostasis in conjunction of reversal of Na+/Ca2+ exchange (NCXrev). Many important issues remain unresolved. First, the postsynaptic neuronal dendrite is selectively vulnerable to hypoxic-ischemic brain injury. Dendritic beading and injury are an early hallmark of neuronal injury in the absence of neuronal death. Na+ influx and mitochondrial dysfunction are important in the acute dendritic injury. However, it is unknown whether NHE-1 and NCXrev contribute to the selective vulnerability of postsynaptic neuronal dendrites. Secondly, activated microglia produce a "respiratory burst" via NADPH oxidase. Therefore, activation of microglia is associated with a large amount of intracellular H+ generation. But, the role of NHE-1 in regulation of microglial pHi and inflammatory responses following ischemia remains unexplored. In the next stage of our study, we will propose two hypotheses: 1) the robust activity of Na+- dependent H+ extrusion mechanism (NHE) in conjunction with activation of NCXrev contributes to ischemic dendritic injury by excessive accumulation of Na+, Ca2+, and mitochondrial dysfunction; 2) NHE-1 activity is stimulated upon microglia activation to meet the demand of maintaining the optimal pHi for NADPH oxidase function following ischemia. Moreover, NHE1-mediated [Na+]i overload and subsequent activation of NCXrev may elevate [Ca2+]i and enhance the p38 MAPK- and/or NF-¿B-mediated inflammatory responses. Therefore, inhibition of NHE-1 activity pharmacologically or via genetic ablation may offer neuroprotection against the acute cerebral ischemic injury via blocking these cellular events. The hypotheses will be tested in three Aims. The results of the proposed studies will enhance our understanding of the appeared paradoxical role of NHE1 in the CNS following ischemia. This knowledge will be beneficial for developing a more effective approach to stroke treatment.

这是一项修订的竞争更新赠款申请（R01NS48216-A1） Na+/H+交换器同工型1（NHE1）在局灶性缺血损伤中的作用。有限的 有关NHE-1在脑缺血中的作用的信息已知 NHE-1的抑制是对缺血性脑损伤的神经保护作用。在最初 资金期，我们发现NHE-1对于调节somata phi至关重要 皮质星形胶质细胞和神经元。星形胶质细胞和神经元中的NHE-1活性为 在氧气和葡萄糖剥夺后刺激氧化过程（REOX） （OGD）。 NHE-1活性的药物抑制或遗传消融 受保护的细胞免受体外和体内缺血模型的缺血性损害。 过度刺激NHE-1活性导致细胞内Na+和 Na+/Ca2+交换（NCXREV）逆转的CA2+稳态。 许多重要的问题仍未解决。首先，突触后神经元树突 有选择地容易受到低氧缺血性脑损伤的影响。树突串珠和伤害 在没有神经元死亡的情况下，是神经元损伤的早期标志。 Na+影响力和 线粒体功能障碍在急性树突损伤中很重要。但是，是 未知NHE-1和NCXREV是否有助于选择性脆弱性 突触后神经元树突。其次，活化的小胶质细胞产生“呼吸道” 因此，小胶质细胞的激活与大型相关 细胞内H+生成量。但是，NHE-1在小胶质细胞调节中的作用 缺血后的PHI和炎症反应仍然出乎意料。在下一个 我们研究的阶段，我们将提出两个假设：1）Na+ - 的鲁棒活性 依赖性H+扩展机制（NHE）与NCXREV的激活结合 通过过量积累Na+，Ca2+和 线粒体功能障碍； 2）小胶质细胞激活至 满足遵循NADPH氧化酶功能的最佳PHI的需求 缺血。此外，NHE1介导的[Na+] I超载和随后的激活 NCXREV可能会提升[Ca2+] i并增强p38 mapk-和/或nf-nf-nf-介导 炎症反应。因此，通过药物或通过 遗传消融可能会通过针对急性脑缺血性损伤提供神经保护作用 阻止这些细胞事件。假设将以三个目标进行检验。结果 在拟议的研究中，将增强我们对出现悖论作用的理解 在缺血之后中枢神经系统中的NHE1。这些知识将有益于发展 一种更有效的中风治疗方法。