Determining the Role of Junctophilin-2 in Cardiac Disease
确定 Junctophilin-2 在心脏病中的作用
基本信息
- 批准号:9102541
- 负责人:
- 金额:$ 5.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-04-01 至 2016-10-12
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAllelesAllosteric RegulationAnimal ModelArrhythmiaBindingCalciumCardiacCardiac MyocytesCardiomyopathiesCell membraneComplexCouplingDataDefectDevelopmentDiffusionDown-RegulationExhibitsFunctional disorderGene DeliveryGene TransferGeneticGoalsGrowthHealthHeartHeart DiseasesHeart HypertrophyHeart failureHumanHypertrophic CardiomyopathyInheritedLeftLifeLinkMagnetic Resonance ImagingMediatingMembraneMissense MutationMolecularMusMuscle CellsMutationOrganPathogenesisPatientsPhosphorylationPlayProcessProtein KinaseProteinsProteomicsRegulationReportingRoleRyR2Ryanodine ReceptorsSarcoplasmic ReticulumSignal PathwaySignal TransductionStructural ProteinStructureSubcellular structureSystemTertiary Protein StructureTestingTransgenic MiceTransgenic OrganismsVariantVentricularWorkage relatedatrioventricular nodeconstrictionimprovedjunctophilinmouse modelmutantnovelpreventvectorvoltage
项目摘要
DESCRIPTION (provided by applicant): Hypertrophic cardiomyopathy (HCM) is the most-common inherited form of heart disease, characterized by thickening of the left ventricular wall, contractile dysfunction, and potentially fatal arrhythmias. There is extensive evidence that defects in excitation-contraction coupling (ECC) contribute to the pathogenesis of both cardiomyopathy and arrhythmias. Specialized membrane junctions known as 'junctional membrane complexes' (JMC) are important subcellular structures in L-type Ca channels (LTCC) on the plasmalemma communicate with ryanodine receptors (RyR2) on the sarcoplasmic reticulum (SR) to initiate contraction. Little is known about the proteins that govern proper subcellular targeting of Ca channels within JMCs, but junctophilin-2 (JPH2) has been identified as a key candidate. In humans, missense mutations in JPH2 cause HCM, although the molecular mechanisms remain unresolved. We have recently demonstrated that JPH2 also binds to and modulates RyR2 channels in the JMC, but the exact protein domains involved in these interactions are still unknown. Moreover, reduced expression of JPH2 has been reported in patients with HCM and animal models of heart failure, but it is unclear whether loss of JPH2 is directly linked to impaired contractility and/or arrhythmias in failing hearts. We have generated several mouse models with HCM-linked JPH2 mutations or with increased/decreased JPH2 expression levels in the heart. The long-term goal of this project is to define the molecular mechanisms by which JPH2 and associated molecules regulate JMC integrity and EC coupling in normal hearts, and how aberrant JPH2 function causes HCM, heart failure, and arrhythmias. Our overall hypothesis is that in normal hearts JPH2 is required for JMC integrity and the regulation of Ca channels therein, whereas loss of JPH2 function due to downregulation or mutation causes cardiomyopathy, heart failure and arrhythmias. To test this hypothesis, we propose to: In Aim 1, determine the role of JPH2 in organizing key Ca handling proteins within the JMC. - In Aim 2, unravel the mechanisms by which genetic JPH2 variants cause HCM. - In Aim 3, determine if JPH2 downregulation is the cause of loss of TTs/JMCs in heart failure.
描述(由申请人提供):肥厚性心肌病(HCM)是最常见的遗传性心脏病,其特征是左心室壁增厚、收缩功能障碍和潜在致命的心律失常。有大量证据表明,兴奋-收缩耦合(ECC)缺陷参与心肌病和心律失常的发病机制。被称为“连接膜复合物”(JMC)的特殊膜连接是质膜上l型Ca通道(LTCC)中重要的亚细胞结构,它与肌浆网(SR)上的ryanodine受体(RyR2)通信以启动收缩。在jmc中,控制Ca通道亚细胞靶向的蛋白知之甚少,但结膜亲蛋白-2 (JPH2)已被确定为一个关键的候选蛋白。在人类中,JPH2的错义突变引起HCM,尽管分子机制尚不清楚。我们最近已经证明JPH2也结合并调节JMC中的RyR2通道,但参与这些相互作用的确切蛋白质结构域仍然未知。此外,在HCM患者和心力衰竭动物模型中也有JPH2表达降低的报道,但尚不清楚JPH2的缺失是否与心力衰竭患者的收缩力受损和/或心律失常直接相关。我们已经建立了几种具有hcm相关的JPH2突变或心脏中JPH2表达水平增加/减少的小鼠模型。该项目的长期目标是明确JPH2及其相关分子在正常心脏中调控JMC完整性和EC耦合的分子机制,以及异常的JPH2功能如何导致HCM、心力衰竭和心律失常。我们的总体假设是,在正常心脏中,JPH2是JMC完整性和Ca通道调节所必需的,而由于JPH2下调或突变导致的功能丧失会导致心肌病、心力衰竭和心律失常。为了验证这一假设,我们提出:在目标1中,确定JPH2在组织JMC内关键钙处理蛋白中的作用。在Aim 2中,揭示遗传JPH2变异导致HCM的机制。-在Aim 3中,确定JPH2下调是否是心力衰竭中tt / jmc丢失的原因。
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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Xander H.T. Wehrens其他文献
Regulation of the RyR2 Calcium Release Channel by SPEG
- DOI:
10.1016/j.bpj.2018.11.2495 - 发表时间:
2019-02-15 - 期刊:
- 影响因子:
- 作者:
Xander H.T. Wehrens - 通讯作者:
Xander H.T. Wehrens
PO-675-03 HIGH PROTEIN DIET-PROMOTES ATRIAL FIBRILLATION BY ACTIVATING AIM2 INFLAMMASOME
- DOI:
10.1016/j.hrthm.2022.03.451 - 发表时间:
2022-05-01 - 期刊:
- 影响因子:5.700
- 作者:
Jia Song;Xiaolei Wang;Yuriana Aguilar-Sanchez;Luge Li;Xander H.T. Wehrens;Na Li - 通讯作者:
Na Li
GW25-e5168 Impaired Post-Transcriptional Regulation of RyR2 by microRNA-106b-25 Cluster Promotes Atrial Fibrillation
- DOI:
10.1016/j.jacc.2014.06.284 - 发表时间:
2014-10-21 - 期刊:
- 影响因子:
- 作者:
Na Li;David Y. Chiang;Niels Voigt;James F. Martin;Dobromir Dobrev;Xander H.T. Wehrens - 通讯作者:
Xander H.T. Wehrens
Ca SR Leak is Modulated by CaMKII Phosphorylation on RyR2-S2814
- DOI:
10.1016/j.bpj.2009.12.1648 - 发表时间:
2010-01-01 - 期刊:
- 影响因子:
- 作者:
Yi Yang;Laetitia Pereira;Ralph J. van Oort;Xander H.T. Wehrens;Donald M. Bers - 通讯作者:
Donald M. Bers
Inhibition of PKA Phosphorylation of RyR2 Improves Excitation-Contraction Coupling in Dystrophic Cardiomyopathy
- DOI:
10.1016/j.hrthm.2009.09.047 - 发表时间:
2009-11-01 - 期刊:
- 影响因子:
- 作者:
Na Li;Satyam Sarma;Ralph J. van Oort;Darlene Skapura;Xander H.T. Wehrens - 通讯作者:
Xander H.T. Wehrens
Xander H.T. Wehrens的其他文献
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{{ truncateString('Xander H.T. Wehrens', 18)}}的其他基金
Role of Nucleoside-Diphosphate Kinase Signaling in Atrial Fibrillation
核苷二磷酸激酶信号传导在心房颤动中的作用
- 批准号:
10594130 - 财政年份:2023
- 资助金额:
$ 5.21万 - 项目类别:
Junctophilin-2 cleavage in ischemic heart disease
缺血性心脏病中的 Junctophilin-2 裂解
- 批准号:
10614525 - 财政年份:2021
- 资助金额:
$ 5.21万 - 项目类别:
Junctophilin-2 cleavage in ischemic heart disease
缺血性心脏病中的 Junctophilin-2 裂解
- 批准号:
10210774 - 财政年份:2021
- 资助金额:
$ 5.21万 - 项目类别:
Junctophilin-2 cleavage in ischemic heart disease
缺血性心脏病中的 Junctophilin-2 裂解
- 批准号:
10375580 - 财政年份:2021
- 资助金额:
$ 5.21万 - 项目类别:
Determining the Role of Junctophilin-2 in Cardiac Disease
确定 Junctophilin-2 在心脏病中的作用
- 批准号:
8901684 - 财政年份:2014
- 资助金额:
$ 5.21万 - 项目类别:
Determining the Role of Junctophilin-2 in Cardiac Disease
确定 Junctophilin-2 在心脏病中的作用
- 批准号:
9041670 - 财政年份:2014
- 资助金额:
$ 5.21万 - 项目类别:
Determining the Role of Junctophilin-2 in Cardiac Disease
确定 Junctophilin-2 在心脏病中的作用
- 批准号:
8828771 - 财政年份:2014
- 资助金额:
$ 5.21万 - 项目类别:
Determining the Role of Junctophilin-2 in Cardiac Disease
确定 Junctophilin-2 在心脏病中的作用
- 批准号:
8710750 - 财政年份:2014
- 资助金额:
$ 5.21万 - 项目类别:
Regulation of Sarcoplasmic Reticulum Calcium Release in Heart Failure
心力衰竭肌浆网钙释放的调节
- 批准号:
9234581 - 财政年份:2009
- 资助金额:
$ 5.21万 - 项目类别:
CaMKII Regulation of Cardiac Ryanodine Receptors in Atrial Fibrillation
CaMKII 对心房颤动中心脏兰尼定受体的调节
- 批准号:
7837367 - 财政年份:2009
- 资助金额:
$ 5.21万 - 项目类别:
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