Sulfonylurea receptor 1 (SUR1)- A novel therapeutic target in ischemic stroke

磺酰脲受体 1 (SUR1)——缺血性中风的新治疗靶点

• 批准号: 7172568
• 负责人: J. Marc Simard
• 金额: $ 36.05万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-19 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7172568
• 关键词: Adverse effects; Astrocytes; Blood; Blood capillaries; Blood flow; Brain; Brain Hypoxia-Ischemia; C57BL/6 Mouse; Capillary Endothelial Cell; Cations; Cell Death; Cells; Cerebral Edema; Cerebral Ischemia; Condition; Coupled; Data; Disruption; Doctor of Philosophy; Dose; Edema; Endothelial Cells; Extravasation; Family; Functional disorder; Glyburide; Grant; Hypoxia; In Vitro; Inbred SHR Rats; Infarction; Ion Channel; Ischemia; Ischemic Stroke; Knock-out; Link; Matrix Metalloproteinases; Measures; Middle Cerebral Artery Occlusion; Modeling; Mus; Neurological outcome; Neurons; Nuclear Extract; Outcome; Pharmaceutical Preparations; Physiological reperfusion; Property; RNA Interference; Rattus; Regulation; Reperfusion Therapy; Reverse Transcriptase Polymerase Chain Reaction; Risk; Rodent; Rodent Model; Role; SP1 gene; Saline; Series; Staging; Stroke; Structure; Testing; Therapeutic Intervention; Thrombolytic Therapy; Time; Tissues; Transcriptional Activation; Up-Regulation; Water; Western Blotting; abstracting; blood lead; capillary; chromatin immunoprecipitation; cytotoxic; day; inhibitor/antagonist; mortality; novel; novel therapeutics; patch clamp; prevent; protective effect; receptor; research study; serial analysis of gene expression; size; sulfonylurea receptor; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): We discovered a new ion channel in cells from ischemic/hypoxic brain that is a potentially important novel target for therapeutic intervention in stroke. This channel is a non-selective cation channel activated by intracellular Ca2+ and blocked by intracellular ATP (NC Ca-ATP channel) that is not normally expressed in brain, but is expressed under conditions of hypoxia. When opened by depletion of intracellular ATP, this channel is responsible for complete depolarization due to massive Na+ influx, which creates an electrical gradient for Cl- and an osmotic gradient for H2O, resulting in cytotoxic edema and cell death. This channel is unusual because it is the first outside the KATP channel family that is found to be regulated by sulfonylurea receptor-1 (SUR1). Thus, cytotoxic edema and cell death normally induced by ATP depletion are prevented in vitro by the SUR1 blocker, glibenclamide. Using rodent models of permanent focal cerebral ischemia (MCAO), we found that the SUR1 regulatory subunit of this channel is up-regulated in astrocytes, neurons, and capillary endothelial cells following ischemia, and that blocking this receptor using the highly specific blocker, low-dose glibenclamide, reduces stroke size, cerebral edema and mortality, consistent with an important role for SUR1 in formation of cytotoxic and ionic edema. Using a rodent (SHR) model of thromboembolic stroke in which tPA is given 6 hr after stroke, we also obtained preliminary data that co-treatment with glibenclamide at 6 hr reduces tPA-associated hemorrhagic conversion. In this grant, we plan 4 aims to: (SA1) assess the protective effect of low dose glibenclamide in a rat model of thromboembolic stroke, including effects on tissue Na+, water, BBB disruption, hemorrhagic conversion, stroke size and neurological outcome, when tPA plus drug co-treatment are begun at various times after stroke; (SA2) assess the protective effect of SUR1 knockout (SUR1KO mice) on tissue Na+, water, BBB disruption, hemorrhagic conversion, stroke size and neurological outcome after temporary MCAO; (SA3) test the hypothesis that SUR1 upregulation in stroke is related to NCCa-ATP channel expression, and characterize channel properties in endothelial cells and neurons at neutral and at low pH; (SA4) identify transcription factors responsible for SUR1 expression in ischemia/hypoxia, including use of serial analysis of gene expression (SAGE) for assessment of tissue-specific transcription factors. (End of Abstract)

描述（由申请人提供）： 我们从缺血/低氧大脑中发现了一个新的离子通道，这是中风治疗干预的潜在重要新颖靶标。该通道是一种非选择性阳离子通道，由细胞内Ca2+激活，并被细胞内ATP（NC CA-ATP通道）阻塞，通常在大脑中不表达，但在缺氧条件下表达。当通过细胞内ATP耗竭打开时，该通道负责由于大量Na+流入而完全去极化，这会为H2O的CL-和渗透梯度产生电梯度，从而导致细胞毒性水肿和细胞死亡。该通道是不寻常的，因为它是KATP通道家族以外的第一个被发现受磺酰脲受体1（SUR1）调节的通道。因此，SUR1阻断剂Glibenclamide在体外预防了通常由ATP耗竭诱导的细胞毒性水肿和细胞死亡。 Using rodent models of permanent focal cerebral ischemia (MCAO), we found that the SUR1 regulatory subunit of this channel is up-regulated in astrocytes, neurons, and capillary endothelial cells following ischemia, and that blocking this receptor using the highly specific blocker, low-dose glibenclamide, reduces stroke size, cerebral edema and mortality, consistent with an important role for SUR1在细胞毒性和离子水肿的形成中。使用啮齿动物（SHR）模型的血栓栓塞中风模型，中风后6小时给出了TPA，我们还获得了初步数据，该数据在6小时时与Glibenclamide共同处理，降低了与TPA相关的出血转化率。在这笔赠款中，我们计划4的目的是：（SA1）在血栓栓塞中风的大鼠模型中评估低剂量的glibenclamide的保护作用，包括对组织Na+的影响，水，BBB的破坏，中风转化，中风大小和神经学结果，当TPA PLES PLES PLUS药物共同创建均在各种情况下进行; （SA2）评估SUR1敲除（SUR1KO小鼠）对临时MCAO后的SUR1敲除（SUR1KO小鼠）对组织NA+，水，BBB破坏，出血转化，中风大小和神经系统结果的保护作用； （SA3）检验以下假设：中风中的SUR1上调与NCCA-ATP通道的表达有关，并表征中性和低pH值处的内皮细胞和神经元中的通道性质； （SA4）确定负责SUR1表达缺血/缺氧的转录因子，包括使用基因表达（SAGE）的系列分析来评估组织特异性转录因子。 （抽象的结尾）