Mechanisms of L-type Calcium Channel Regulation in Heart Health and Disease
L 型钙通道在心脏健康和疾病中的调节机制
基本信息
- 批准号:10734121
- 负责人:
- 金额:$ 64.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-31 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAddressAdrenergic ReceptorAgonistAngiotensinsAnimal ModelAttenuatedBindingBiophysicsBypassC-terminalCa(2+)-Calmodulin Dependent Protein KinaseCalcium ChannelCardiac healthCessation of lifeClinical TrialsCyclic AMP-Dependent Protein KinasesDataDisease modelDiureticsDown-RegulationEFRACFailureFamilyFamily suidaeGoalsHealthHeartHeart DiseasesHeart failureHumanHydrophobicityInotropismKineticsKnock-inKnock-in MouseKnock-outL-Type Calcium ChannelsMacromolecular ComplexesMeasuresMediatingModelingModificationMolecularMonomeric GTP-Binding ProteinsMouse StrainsMusMyocardial ContractionPathologicPatientsPhosphatidylinositol 4,5-DiphosphatePhosphorylationPilot ProjectsPreparationReceptor SignalingRegulationRiskRisk ReductionSafetySarcomeresSignal PathwaySignal TransductionSliceStructural ModelsStructureSympathomimeticsTestingTherapeuticTherapeutic UsesUnited StatesWorkantagonistearly phase clinical trialfollow-upgain of functiongenetic approachimprovedin vivoloss of functionmembernovelnovel therapeuticspharmacologicphosphoric diester hydrolaseprotein complexresponsesensorstoichiometrysuccesstranslational potentialvoltage
项目摘要
Inotropic support for hearts progressing towards failure represents an unmet need. Direct attempts to improve
systolic function by activating -adrenergic receptor (-AR) signaling increases associated risk of heart failure
and death. Calcitropes (agents influencing Ca2+ handling) that bypass -AR signaling are not necessarily
proarrhythmic. Our working global hypothesis based on our recent and ongoing work studying RAD regulation
of the L-type Ca2+ channel (LTCC) is that bypassing -AR signaling to increase Ca2+-induced Ca2+ release (CICR)
provides safe, stable gain of function to counter heart failure progression. In this application we focus on the
mechanisms of Rad – LTCC interactions as a novel means to instill inotropic support to the heart. The LTCC is
a macromolecular hub that integrates multiple signaling pathways including protein kinase A (PKA) and Ca2+-
calmodulin kinase II (CaMKII). RAD is a member of the RGK family of monomeric G-proteins. RAD binds to
auxiliary CaV2 and CaV1.2, the pore-forming subunit of the LTCC. Deletion, or phosphorylation of RAD causes
LTCC current (ICa,L) modulation and facilitation. Modulation of ICa,L is commonly observed after -AR signaling to
activate PKA; facilitation is caused by CaMKII activation. In Specific Aim 1 we will dissect how RAD integrates
each of these signaling pathways using a combination of pharmacological and genetic approaches. In Specific
Aim 2 we will explore RAD – CaV1.2 structure-function using knock-in models of genetically modified mice that
allow us to explore RAD – LTCC effects retaining native stoichiometry of the LTCC heteromultimeric protein
complex. Specific Aim 3 explores RAD – LTCC interplay as an approach to attenuate progression of heart failure.
To achieve these goals, we will integrate findings among Aims using in vivo, ex vivo and cellular/molecular
approaches in animal models. Ex vivo human heart slices will be tested to evaluate the translational potential of
RAD – LTCC regulation in heart health and disease.
对心脏逐渐衰竭的正性肌力支持是一种未满足的需求。直接尝试改善
通过激活β-肾上腺素能受体(β-AR)信号传导的收缩功能增加心力衰竭的相关风险
与死绕过β-AR信号传导的钙索(影响Ca 2+处理的试剂)不一定是
预防性的我们的工作全球假设基于我们最近和正在进行的研究RAD调节的工作
L-型钙通道(LTCC)的主要作用是通过旁路β-AR信号增加钙诱导的钙释放(CICR)。
提供安全、稳定的功能恢复,以对抗心力衰竭进展。在本应用程序中,我们重点关注
Rad - LTCC相互作用的机制作为向心脏灌输正性肌力支持的新手段。LTCC是
一个大分子枢纽,整合了多种信号通路,包括蛋白激酶A(PKA)和Ca 2 +-
钙调蛋白激酶II(CaMK II)。RAD是单体G蛋白RGK家族的成员。RAD绑定到
辅助CaV1.2和CaV1.2是LTCC的成孔亚基。RAD的缺失或磷酸化导致
LTCC电流(伊卡,L)调节和促进。伊卡,L的调节通常在β-AR信号传导后观察到,
激活PKA;易化由CaMKII激活引起。在具体目标1中,我们将剖析RAD如何集成
这些信号通路中的每一个都使用药理学和遗传学方法的组合。在特定
目的2:我们将使用基因修饰小鼠的敲入模型来探索RAD-CaV 1. 2的结构-功能,
允许我们探索RAD-LTCC效应,保留LTCC异多聚体蛋白的天然化学计量
复杂.具体目标3探讨了RAD-LTCC相互作用作为减缓心力衰竭进展的方法。
为了实现这些目标,我们将使用体内,离体和细胞/分子生物学方法整合目的之间的发现,
动物模型的方法。将测试离体人心脏切片以评估以下的翻译潜力:
RAD-LTCC调节心脏健康和疾病。
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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Jonathan Satin其他文献
Jonathan Satin的其他文献
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{{ truncateString('Jonathan Satin', 18)}}的其他基金
Mechanisms of Long-term Cardiac Ion Channel Regulation
心脏离子通道的长期调节机制
- 批准号:
8290229 - 财政年份:2009
- 资助金额:
$ 64.37万 - 项目类别:
Mechanisms of Long-term Cardiac Ion Channel Regulation
心脏离子通道的长期调节机制
- 批准号:
8469331 - 财政年份:2009
- 资助金额:
$ 64.37万 - 项目类别:
Mechanisms of Long-term Cardiac Ion Channel Regulation
心脏离子通道的长期调节机制
- 批准号:
7583426 - 财政年份:2009
- 资助金额:
$ 64.37万 - 项目类别:
Mechanisms of Long-term Cardiac Ion Channel Regulation
心脏离子通道的长期调节机制
- 批准号:
8069300 - 财政年份:2009
- 资助金额:
$ 64.37万 - 项目类别:
Mechanisms of Long-term Cardiac Ion Channel Regulation
心脏离子通道的长期调节机制
- 批准号:
7758785 - 财政年份:2009
- 资助金额:
$ 64.37万 - 项目类别:
Mechanisms of Long-term Cardiac Ion Channel Regulation
心脏离子通道的长期调节机制
- 批准号:
6673929 - 财政年份:2003
- 资助金额:
$ 64.37万 - 项目类别:
Mechanisms of Long-term Cardiac Ion Channel Regulation
心脏离子通道的长期调节机制
- 批准号:
6900271 - 财政年份:2003
- 资助金额:
$ 64.37万 - 项目类别:
Mechanisms of Long-term Cardiac Ion Channel Regulation
心脏离子通道的长期调节机制
- 批准号:
7631067 - 财政年份:2003
- 资助金额:
$ 64.37万 - 项目类别:
Mechanisms of Long-term Cardiac Ion Channel Regulation
心脏离子通道的长期调节机制
- 批准号:
6772662 - 财政年份:2003
- 资助金额:
$ 64.37万 - 项目类别:
Mechanisms of Long-term Cardiac Ion Channel Regulation
心脏离子通道的长期调节机制
- 批准号:
7076186 - 财政年份:2003
- 资助金额:
$ 64.37万 - 项目类别:
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