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: 8066609
• 负责人: Dandan Sun
• 金额: $ 15.11万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 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 2011-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8066609
• 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; Health; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This proposal is to study the role of Na+/H+ exchanger isoform 1 (NHE1) in cerebral ischemic damage. The long-term goal of the research is to understand the role of ion transport proteins in disruption of ion homeostasis following ischemia and to determine whether these ion transport proteins are potential targets for developing more effective stroke treatments.

描述（由申请人提供）：这是修订的竞争性更新赠款申请（R01NS48216-A1），用于研究Na+/H+交换器同工型1（NHE1）在局灶性缺血性损害中的作用。关于NHE-1在脑缺血中的作用以及NHE-1的抑制是否对缺血性脑损伤具有神经保护作用，已知有限的信息。在最初的资金期间，我们发现NHE-1对于调节皮质星形胶质细胞和神经元中的Somata Phi至关重要。在氧气和葡萄糖剥夺（OGD）后，刺激星形胶质细胞和神经元中的NHE-1活性。在体外和体内缺血模型中，NHE-1活性的药理抑制作用或遗传消融受到缺血性损害的影响。过度刺激NHE-1活性导致细胞内Na+和Ca2+稳态的失调，以逆转Na+/Ca2+交换（NCXREV）的逆转。许多重要的问题仍未解决。首先，突触后神经元树突有选择性地容易受到低氧缺血性脑损伤的影响。在没有神经元死亡的情况下，树突状珠子和损伤是神经元损伤的早期标志。 Na+流入和线粒体功能障碍在急性树突状损伤中很重要。但是，尚不清楚NHE-1和NCXREV是否有助于突触后神经元树突的选择性脆弱性。其次，活化的小胶质细胞通过NADPH氧化酶产生“呼吸爆发”。因此，小胶质细胞的激活与大量细胞内H+产生有关。但是，缺血后NHE-1在小胶质细胞PHI和炎症反应调节中的作用仍未得到探索。在下一阶段，我们将提出两个假设：1）Na+ - 依赖性H+挤出机制（NHE）的鲁棒活性与NCXREV的激活结合起来，从而导致缺血性树突状损伤Na+，Ca2+，Ca2+和Mitochondirial功能障碍； 2）小胶质细胞激活时刺激NHE-1活性，以满足缺血后NADPH氧化酶功能的最佳PHI的需求。此外，NHE1介导的[Na+] I过载和随后的NCXREV激活可能会升高[Ca2+] I并增强p38 MAPK-和/或NF-：B介导的炎症反应。因此，通过阻断这些细胞事件，在药理学或通过遗传消融的NHE-1活性抑制可能为急性脑缺血性损伤提供神经保护作用。假设将以三个目标进行检验。拟议的研究的结果将增强我们对缺血后CNS中NHE1出现的悖论作用的理解。这些知识将有助于开发更有效的中风治疗方法。公共卫生相关性：该建议是研究Na+/H+交换器同工型1（NHE1）在脑缺血性损害中的作用。该研究的长期目标是了解缺血后离子转运蛋白在干扰离子稳态中的作用，并确定这些离子转运蛋白是否是开发更有效的中风治疗的潜在靶标。