The Role of Na+/H+ exchanger in Cerebral Ischemia

Na/H交换器在脑缺血中的作用

• 批准号: 7342903
• 负责人: Dandan Sun
• 金额: $ 18.6万
• 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 2009-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7342903
• 关键词: Ablation; Acidosis; Animal Experiments; Astrocytes; Attenuated; Brain Injuries; Calpain; Carrier Proteins; Caspase; Cell Death; Cells; Cerebral Ischemia; Cerebrum; Cessation of life; Clinical Trials; Coculture Techniques; Development; Disruption; Dose; Edema; Endopeptidases; Exhibits; Free Radical Formation; Free Radicals; Genetic; Glucose; Glutamates; Goals; Homeostasis; In Vitro; Infarction; Ions; Ischemia; Ischemic Brain Injury; Lead; Mediating; Modeling; Mus; Mutation; Myocardial Ischemia; Neurologic; Neurons; Numbers; Oxygen; Peptide Hydrolases; Phospholipase; Physiological reperfusion; Play; Protein Isoforms; Recovery; Regulation; Reperfusion Therapy; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Stroke; Swelling; Testing; cariporide; cell injury; cytotoxic; deprivation; excitotoxicity; inhibitor/antagonist; insight; mutant; neuroprotection; programs

DESCRIPTION (provided by applicant): The long-term goal of our research is to understand the cellular mechanisms underlying cerebral ischemic damage and provide insights for development of effective treatment for stroke. Our previous studies demonstrate that a Na-dependent Cl transporter plays an important role in disruption of ion homeostasis in cerebral ischemia and contributes to cytotoxic edema and ischemic damage. In this study, we will investigate the role of Na/H exchanger isoform 1 (NHE1) in ischemic damage. It is unknown whether NHE1 activity contributes to ion perturbation in cerebral ischemia and whether inhibition of NHE1 is neuroprotective against ischemic brain damage. Our preliminary study revealed that NHE1 is essential in regulation of pHi in astrocytes and neurons. Either pharmacological inhibition or genetic ablation of NHE1 activity delayed pHi regulation and significantly reduced Na+ accumulation in astrocytes and neurons following in vitro ischemia (oxygen and glucose deprivation, OGD). Moreover inhibition of NHE1 with a potent inhibitor HOE 642 reduced infarct volume by 40% following focal ischemia. The cellular mechanisms underlying this protection are not well understood. Therefore, an extensive study of NHE1 in cerebral ischemia is warranted. We hypothesize that NHE1 activity in astrocytes and neurons is stimulated following focal ischemia. Excessive stimulation of NHE1 will lead to the intracellular Na+ overload, which in turn can cause the rise of intracellular Ca2+ (through reduced Ca efflux and/or increased Ca influx via the reversed Na/Ca exchange). Thus, NHE1 activity contributes to cerebral ischemic damage in part by disruption of intracellular Na+ and Ca2+ homeostasis. These hypotheses will be tested by three Aims: 1. Determine the role of NHE1 in pHi regulation, intracellular Na+ and Ca2+ overload, swelling, and cell damage in astrocytes following OGD. 2. Investigate the contribution of NHE1 to ischemic neuronal death. 3. Investigate whether pharmacological inhibition and genetic ablation of NHE1 reduces brain damage in mice following transient focal ischemia.

描述（由申请人提供）：我们研究的长期目标是了解脑缺血性损害的细胞机制，并为开发有效治疗的中风治疗提供了见解。我们以前的研究表明，NA依赖性CL转运蛋白在破坏脑缺血中的离子稳态中起着重要作用，并有助于细胞毒性水肿和缺血性损伤。在这项研究中，我们将研究Na/H交换器同工型1（NHE1）在缺血性损伤中的作用。尚不清楚NHE1活性是否有助于脑缺血的离子扰动，以及NHE1的抑制是否对缺血性脑损伤具有神经保护作用。我们的初步研究表明，NHE1对于调节星形胶质细胞和神经元的PHI至关重要。在体外缺血后，NHE1活性的药理抑制作用或NHE1活性的遗传消融延迟了PHI调控，并且在星形胶质细胞和神经元中的Na+积累显着降低（氧和葡萄糖剥夺，OGD）。此外，用有效的抑制剂HOE 642对NHE1的抑制作用降低了局灶性缺血后40％。该保护基础的细胞机制尚不清楚。因此，有必要对NHE1进行广泛的研究。我们假设在局灶性缺血后刺激星形胶质细胞和神经元中的NHE1活性。过度刺激NHE1将导致细胞内Na+超负荷，这又可能导致细胞内Ca2+的上升（通过减少Ca外排和/或通过反向的Na/Ca交换增加CA涌入）。因此，NHE1活性在部分破坏细胞内Na+和Ca2+稳态中有助于脑缺血性损害。这些假设将通过三个目标进行检验：1。确定NHE1在OGD后星形胶质细胞中PHI调控，细胞内Na+和Ca2+过载，肿胀和细胞损伤中的作用。 2。研究NHE1对缺血性神经元死亡的贡献。 3。研究NHE1的药理抑制和遗传消融是否会减少短暂性局灶性缺血后小鼠的脑损伤。