Ca Channels, TRP Channels & Vasomotor Function in Cerebral Arterioles
Ca 通道、TRP 通道
基本信息
- 批准号:7998811
- 负责人:
- 金额:$ 38.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-08-01 至 2015-07-31
- 项目状态:已结题
- 来源:
- 关键词:AstrocytesBlood VesselsBlood flowBrainCalciumCaliberCell physiologyCellsCerebrovascular CirculationCerebrovascular DisordersCerebrumCommunicationCouplingDataDrug Delivery SystemsEndothelial CellsEndotheliumEventFeedbackFluorescent DyesFrequenciesFunctional disorderGoalsIon ChannelIschemiaMeasuresMediatingMembrane PotentialsMicrocirculationModelingMolecularMuscle CellsMuscle functionPathway interactionsPerfusionPhysiologicalPlayReceptor ActivationRegulationReperfusion TherapyRoleSignal TransductionSmooth MuscleSmooth Muscle MyocytesStimulusSubarachnoid HemorrhageTestingTotal Internal Reflection FluorescentVasoconstrictor AgentsVasodilator AgentsVasomotorabstractingarteriolebasecell typecerebrovascularconstrictioninsightlarge-conductance calcium-activated potassium channelspatch clamppressurepreventreceptorresearch studyvasoconstrictionvoltage
项目摘要
ABSTRACT
Parenchymal arterioles (PAs) play a critical role in assuring that appropriate local cerebral blood flow
and perfusion pressure are maintained under a variety of conditions. This essential physiological
function is regulated by tight communication among the various cells that form the cerebrovascular
unit (endothelium, smooth muscle, and astrocytes) and clearly involves the dynamic regulation of
intracellular [Ca^"*] in each cell type. The focus of this project is on parenchymal arteriolar smooth
muscle cell calcium (Ca^*) signaling, which is the ultimate determinant of myocyte excitability,
vasomotor tone, and blood flow in the microcirculation of the brain. Voltage-dependent Ca^* (Cav)
channels are central integrators of both vasodilator and vasoconstrictor stimuli in the cerebral
circulation. In addition, Transient Receptor Potential (TRP) channels transduce vasoactive signals,
including intravascular pressure and receptor activation, to directly and indirectly modulate
intracellular Ca^* in the vasculature. However, virtually nothing is known about the functional
contributions of these channels in PAs. Thus the overarching goal of this project is to reveal the
molecular mechanisms of vascular control of PAs involving Cav and TRP channels. Based on our
preliminary data we have formulated a model of excitation-contraction coupling in arteriolar smooth
muscle in which E-C coupling is facilitated in two ways: 1) High activity of Ca^* entry pathways
mediated or modulated by Cav, TRPC6, TRPM4, and TRPV4 channels, and by PCK, and 2)
suppressed negative feedback input normally provided by Ca^* spark and BK channel activity. To
assess the specific roles of Cav and TRP channels in generating Ca^* signals, Ca^* will be measured with fluorescent dyes using confocal and TIRF microscopy, approaches developed or implemented by our team. Vasomotor function will be measured in isolated, pressurized parenchymal arteriole segments, and ion channel function will be studied using patch clamp approaches. Information and insights gained will be coordinated with studies focused on normal endothelial cell function in PAs (M. Nelson, Project 1) and used to understand how arteriolar smooth muscle function, in general, and the expression and activity of various vasoconstrictor mechanisms, in particular, may be altered following ischemia and reperfusion (M. Cipolla, Project 3) and subarachnoid hemorrhage (G. Wellman, Project 4). Elucidation of the roles of TRP channels and their interaction with Cav channels in smooth muscle function and dysfunction as detailed in this project represents a unique opportunity to define a new set of pharmacologically relevant drug targets aimed at treating and preventing cerebrovascular
disorders.
摘要
脑实质小动脉(PA)在确保适当的局部脑血流中起着关键作用
和灌注压在各种条件下维持。这种基本的生理
脑血管的功能是由形成脑血管的各种细胞之间的紧密联系来调节的
单位(内皮,平滑肌和星形胶质细胞),并明确涉及动态调节,
在每种细胞类型中的细胞内[Ca^+*]。本项目的重点是实质小动脉光滑
肌细胞钙(Ca^*)信号传导,其是肌细胞兴奋性的最终决定因素,
血管张力和大脑微循环中的血流。电压依赖性Ca^*(Cav)
通道是脑内血管扩张和血管收缩刺激的中枢整合者
流通此外,瞬时受体电位(TRP)通道传递血管活性信号,
包括血管内压力和受体激活,以直接和间接地调节
血管中的细胞内Ca^*。然而,几乎没有什么是已知的功能,
这些通道在PA中的贡献。因此,该项目的首要目标是揭示
涉及Cav和TRP通道的PA的血管控制的分子机制。基于我们
初步数据,我们制定了一个模型的兴奋收缩耦合在小动脉平滑
在肌肉中,E-C偶联以两种方式促进:1)高活性的Ca^* 进入途径
由Cav、TRPC 6、TRPM 4和TRPV 4通道以及由PCK介导或调节,以及2)
抑制通常由Ca^* 火花和BK通道活动提供的负反馈输入。到
为了评估Cav和TRP通道在产生Ca^* 信号中的特定作用,将使用我们团队开发或实施的共聚焦和TIRF显微镜用荧光染料测量Ca^*。将在分离的加压实质小动脉段中测量血管功能,并将使用膜片钳方法研究离子通道功能。所获得的信息和见解将与PA中正常内皮细胞功能的研究相协调(M。纳尔逊,项目1),并用于理解在缺血和再灌注后,小动脉平滑肌功能,特别是各种血管收缩机制的表达和活性如何改变(M. Cipolla,项目3)和蛛网膜下腔出血(G。Wellman,项目4)。阐明TRP通道的作用及其与Cav通道在平滑肌功能和功能障碍中的相互作用,如本项目所述,代表了一个独特的机会,可以定义一组新的与血管相关的药物靶点,旨在治疗和预防脑血管疾病。
紊乱
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JOSEPH ELLIOTT BRAYDEN其他文献
JOSEPH ELLIOTT BRAYDEN的其他文献
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{{ truncateString('JOSEPH ELLIOTT BRAYDEN', 18)}}的其他基金
MECHANISMS OF CEREBRAL RESISTANCE ARTERY CONTRACTION
脑阻力动脉收缩的机制
- 批准号:
2685534 - 财政年份:1997
- 资助金额:
$ 38.85万 - 项目类别:
MECHANISMS OF CEREBRAL RESISTANCE ARTERY CONTRACTION
脑阻力动脉收缩的机制
- 批准号:
2840176 - 财政年份:1997
- 资助金额:
$ 38.85万 - 项目类别:
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