Mechanisms of Coronary Vasomotor Control
冠状动脉血管舒缩控制机制
基本信息
- 批准号:8578656
- 负责人:
- 金额:$ 35.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-08-01 至 2017-05-31
- 项目状态:已结题
- 来源:
- 关键词:4-AminopyridineAddressAdenosineAerobicApicalArteriesAutomobile DrivingBlood VesselsBlood flowCardiacCardiac MyocytesCardiomyopathiesCell RespirationChronicClinical TrialsCoronaryCoronary heart diseaseCouplesCouplingDataDeteriorationDevelopmentDiabetic AngiopathiesDrug usageElectrocardiogramElectrophysiology (science)FamilyFunctional disorderGoalsHeartHydrogen PeroxideHypoxiaImpairmentIn VitroIon ChannelKnockout MiceKv1.2&apos channelLinkMeasuresMediatingMetabolicMetabolismMitochondriaMusMyocardialMyocardial IschemiaMyocardial perfusionMyocardial tissueMyocardiumOxidation-ReductionPatientsPhenotypePhysiologyPlayProcessProductionRegulationReportingRoleSignal TransductionSmooth MuscleSyndromeSystemTestingTetanus Helper PeptideThinkingTransgenic OrganismsVascular Smooth MuscleVasodilationVasomotorWorkarterioledb/db mousediabeticdiabetic cardiomyopathyfeedingfunctional disabilitygain of functionheart metabolismin vivoindexingloss of functionmemberpreventpublic health relevanceresearch studysensortissue oxygenation
项目摘要
DESCRIPTION (provided by applicant): The overarching aim of this proposal is to elucidate vascular effectors that transduce metabolic signals that enable the connection of flow to cardiac metabolism-metabolic dilation. The heart is dependent on metabolic dilation for aerobic energy production because anaerobic reserve is virtually non-existent; however, the effectors responsible for coupling flow to metabolism in the heart remain unidentified. The matching of flow to metabolism is important and may play a role in microvascular diseases in the heart. We have suggested that Kv channels transduce the H2O2 metabolic signal into redox- mediated coronary metabolic vasodilation. Because certain members of the Kv1 family of channels are redox sensitive (e.g., Kv1.2, 1.3 and 1.5), our first goal will determine, which redox sensing Kv channels transduce metabolic signals to flow in the heart. This aim will be tested using loss and gain of function approaches. Loss of function will use mice null for Kv1.5 and 1.3 channels, and heterozygous null for Kv1.2 channels (Kv1.2-/- is lethal), and gain of function will study of expression of the specific ion channel using a smooth muscle specific Tet On system driving expression of the Kv channel. We have found that metabolic dilation in the diabetic db/db mouse is impaired and that expression of Kv1.2, 1.3, and 1.5 channels is substantially decreased in arteries of these mice. Our goal in the second aim is to perform gain of function studies in db/db mice by expressing Kv1.5, 1.2 and/or Kv1.3 channels using the Tet inducible system in smooth muscle. Our overall strategy is to measure the relationship between cardiac work, and myocardial blood flow and tissue oxygenation along with evaluating measures of cardiac function and myocardial ischemia. We also will perform in vitro studies to determine the production of vasoactive metabolites from cardiac myocytes, vascular reactivity of isolated arterioles and electrophysiological parameters in smooth muscle. This integrated approach-from electrophysiology to in vivo flow regulation should enable answers regarding basic coronary physiology and flow regulation, as well as potential therapies for diabetic cardiomyopathy.
描述(由申请人提供):本提案的主要目的是阐明传递代谢信号的血管效应器,从而使血流与心脏代谢-代谢扩张联系在一起。心脏依靠代谢扩张来产生有氧能量,因为实际上不存在无氧储备;然而,负责将心脏中的血流与新陈代谢耦合的效应器仍未确定。血流与新陈代谢的匹配很重要,并可能在心脏微血管疾病中发挥作用。我们认为Kv通道将H_2O_2代谢信号转导为氧化还原介导的冠脉代谢血管扩张。由于KV1家族的某些成员对氧化还原敏感(例如,Kv1.2、1.3和1.5),我们的第一个目标将确定哪些氧化还原敏感Kv通道转导代谢信号在心脏中流动。这一目标将使用功能损失和收益方法进行测试。功能丧失将利用小鼠对Kv1.5和1.3通道的缺失,以及对Kv1.2通道的杂合性缺失(Kv1.2-/-是致命的),而功能的获得将研究使用平滑肌特异性Tet对Kv通道的系统驱动表达的特定离子通道的表达。我们发现糖尿病db/db小鼠的代谢扩张功能受损,Kv1.2、1.3和1.5通道在这些小鼠的动脉中的表达显著减少。第二个目标是利用Tet诱导系统在db/db小鼠中表达Kv1.5、1.2和/或Kv1.3通道,从而在db/db小鼠中进行功能研究。我们的总体战略是测量心脏做功与心肌血流量和组织氧合之间的关系,以及评估心功能和心肌缺血的措施。我们还将进行体外研究,以确定心肌细胞血管活性代谢物的产生,分离小动脉的血管反应性和平滑肌的电生理参数。这种从电生理学到体内血流调节的综合方法应该能够回答基本的冠脉生理学和血流调节,以及糖尿病心肌病的潜在治疗方法。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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WILLIAM M CHILIAN其他文献
WILLIAM M CHILIAN的其他文献
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{{ truncateString('WILLIAM M CHILIAN', 18)}}的其他基金
The critical role of the coronary microcirculation in heart failure
冠状动脉微循环在心力衰竭中的关键作用
- 批准号:
9383841 - 财政年份:2017
- 资助金额:
$ 35.81万 - 项目类别:
What mechanisms underlie coronary collateral growth?
冠状动脉侧枝生长的机制是什么?
- 批准号:
9220295 - 财政年份:2016
- 资助金额:
$ 35.81万 - 项目类别:
Reactive Oxygen Species in Coronary Collateral Growth
冠状动脉侧枝生长中的活性氧
- 批准号:
8267619 - 财政年份:2009
- 资助金额:
$ 35.81万 - 项目类别:
Reactive Oxygen Species in Coronary Collateral Growth
冠状动脉侧枝生长中的活性氧
- 批准号:
7898715 - 财政年份:2009
- 资助金额:
$ 35.81万 - 项目类别:
Reactive Oxygen Species in Coronary Collateral Growth
冠状动脉侧枝生长中的活性氧
- 批准号:
8471748 - 财政年份:2009
- 资助金额:
$ 35.81万 - 项目类别:
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