Regulation of calcium-activated potassium channels by blood breakdown products
血液分解产物对钙激活钾通道的调节
基本信息
- 批准号:7477123
- 负责人:
- 金额:$ 35.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1998
- 资助国家:美国
- 起止时间:1998-05-01 至 2011-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectBehaviorBilirubinBiliverdineBindingBinding SitesBloodBlood ClotBlood VesselsBlood coagulationBrainBrain hemorrhageCalciumCalcium-Activated Potassium ChannelCarbon MonoxideCerebral hemisphere hemorrhageCerebrovascular SpasmComplementConstriction procedureCouplingDevelopmentDisruptionDoseEquilibriumFigs - dietaryGeneticGoalsHemeHemorrhageHypertensionInterventionIon ChannelIon Channel ProteinIsometric ExerciseKnockout MiceLinkMeasurementMembraneModelingMolecularMorbidity - disease rateMusMuscleMuscle ContractionNADPPhenylephrinePhysiologicalPhysiologyPlayPotassium ChannelProteinsRegulationRelaxationResearchResearch PersonnelRestRoleSmooth Muscle MyocytesTestingTherapeuticTimeVascular DiseasesVascular Smooth MuscleVasospasmWild Type Mouseinnovationinsightmortalitynovelnovel therapeuticsoxidationprogramsresearch studyresponsesensorvasoconstrictionvoltage
项目摘要
DESCRIPTION (provided by applicant): Many of us will be eventually afflicted with vascular disorders, such as hypertension and brain hemorrhage. Cerebral hemorrhage is often followed by delayed cerebral vasospasm, which itself represents a significant morbidity and mortality factor. Cerebral vasospasm is characterized by a long-lasting abnormal contraction of vascular smooth muscle cells. Previous studies have suggested that blood breakdown products, such as heme, CO, bilirubin and bilirubin oxidation end products (BOXes), may be involved but the underlying mechanism has remained elusive. Among the many proteins involved in regulation of vascular smooth muscles, large-conductance calcium- and voltage-activated (Slo1 BK) potassium channels play a critical role in vascular relaxation. The importance of Slo1 channels in regulation of vascular tone suggests that many disorders of vascular relaxation, including cerebral vasospasm, may involve dysregulation of Slo1 channels. Because bilirubin and bilirubin oxidation end products are implicated in vasospasm and Slo1 channels play a critical role in regulation of vascular tone, we hypothesize that heme catabolic products may contribute to cerebral vasospasm by modulating Slo1 channels. To test this hypothesis, effects of heme catabolic products (CO, bilirubin and bilirubin oxidation end products) on the Slo1 channel function are electrophysiologically and quantitatively investigated using macroscopic and single-channel ionic current and macroscopic gating current measurements. These biophysical measurements are complemented with physiological isometric force measurements using aortic blood vessels from wild-type and Slo1 knockout mice. The results expected from the research program proposed will establish a new paradigm of CO sensing by Slo1 and will highlight Slo1 channels as an important causal link between cerebral hemorrhage and cerebral vasospasm. These novel conceptual frameworks in turn suggest new therapeutic strategies for disorders of vascular relaxation including delayed cerebral vasospasm.
描述(由申请人提供):我们中的许多人最终会受到血管疾病的折磨,如高血压和脑出血。脑出血后常发生迟发性脑血管痉挛,其本身就是一个重要的发病率和死亡率因素。脑血管痉挛的特征是血管平滑肌细胞的长期异常收缩。以前的研究表明,血液分解产物,如血红素,CO,胆红素和胆红素氧化终产物(BOXes),可能参与,但潜在的机制仍然难以捉摸。在参与调节血管平滑肌的许多蛋白质中,大电导钙和电压激活(Slo1 BK)钾通道在血管舒张中起关键作用。Slo1通道在调节血管张力中的重要性表明,许多血管舒张障碍,包括脑血管痉挛,可能涉及Slo1通道的失调。由于胆红素和胆红素氧化终产物与血管痉挛有关,Slo1通道在调节血管张力中起着关键作用,因此我们假设血红素分解代谢产物可能通过调节Slo1通道而导致脑血管痉挛。为了验证这一假设,血红素分解代谢产物(CO,胆红素和胆红素氧化终产物)对Slo1通道功能的影响进行电生理和定量研究,使用宏观和单通道离子电流和宏观门控电流测量。这些生物物理测量与使用野生型和Slo1敲除小鼠的主动脉血管的生理等长力测量相补充。从研究计划提出的预期结果将建立一个新的范式的CO传感的Slo1,并将突出Slo1通道作为一个重要的因果关系之间的联系,脑出血和脑血管痉挛。这些新的概念框架反过来又为包括迟发性脑血管痉挛在内的血管舒张障碍提出了新的治疗策略。
项目成果
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TOSHINORI HOSHI其他文献
TOSHINORI HOSHI的其他文献
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