Novel Functions of the E-C Coupling Structural Protein Junctophilin-2 in the Heart
Novel Functions of the E-C Coupling Structural Protein Junctophilin-2 in the Heart
批准号:
10689197
负责人:
Long-Sheng Song
金额:
$60.53万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-01-15 至 2024-08-31
关键词:
Animal ModelBiochemicalCalpainCardiacCardiac MyocytesCardiovascular DiseasesCell Culture TechniquesCell NucleusCell membraneCell modelComplexCouplingDataDevelopmentDiseaseDown-RegulationEndowmentFunctional disorderFundingFutureGenerationsGeneticGenetic TranscriptionGoalsHeartHeart DiseasesHeart failureHomeostasisHumanKnock-in MouseLinkMediatingMediatorMembraneMolecularMusMuscle CellsMutateMutationMutation AnalysisMyocardial InfarctionN-terminalNuclearNuclear ImportNuclear TranslocationOutcomePathogenesisPathologicPathway interactionsPatientsPhosphorylationPhosphotransferasesPhysiologicalPhysiologyPost-Translational Protein ProcessingPrevalenceProcessProductionProteinsProteolysisRegulationRepressionReproducibilityResearchResistanceRoleSarcoplasmic ReticulumSignal PathwaySignal TransductionSiteStressStructural ProteinStructureTestingTherapeuticTranscriptTranscriptional RegulationTreatment FailureTubular formationVentricularbiological adaptation to stresscardioprotectioncardiovascular healthdesignexperimental studyheart functionheart preservationimprovedin vitro Assayin vivoinsightjunctophilinmimeticsmultidisciplinarymutantnoveloverexpressionpreservationpressurepreventresponsetooltranscriptional reprogramming
中文摘要
项目总结
连接蛋白2(JP2)是形成连接偶联所必需的结构蛋白(即,
心脏二联体)位于横形(T)管膜和肌浆网(SR)之间。JP2函数
因此,它是局部控制钙诱导的钙释放和有效收缩的基础。
心肌兴奋-收缩(E-C)偶联过程中的心肌细胞。JP2蛋白水平在衰竭时逐渐下降
人心脏和心力衰竭导致T小管重塑和E-C偶联丧失的动物模型
功能。JP2在E-C偶联位点的下调部分是由于钙激活的特异性切割所致
一种与多种心脏疾病有关的蛋白水解酶。在上一个资助期内,我们
证明了依赖于压力和钙蛋白的JP2裂解释放了一种新的,核转位,N-
末端片段(JP2NT),抑制疾病心脏中的不适应转录重编程,因此
将E-C解偶联信息转化为独特的心脏保护性激发-转录(E-T)偶联
向原子核发出信号。然而,JP2介导的E-C和E-T耦合现象是如何被机械调节的
仍有待确定。我们的新的初步结果表明,在应激条件下,JP2被重复地磷酸化。
心脏靠近负责JP2裂解和JP2NT亚细胞定位的区域。在这场竞争中
续订申请,我们的目标是定义应力诱导的翻译后修饰如何调节结构,
JP2/JP2NT的定位和功能。我们假设JP2NT介导的E-T偶联受到严格调控
通过心脏应激依赖的JP2磷酸化决定JP2对Calain和JP2NT的敏感性
核转位和转录活性。为了验证我们的假设,在目标1中,我们将使用突变分析
和细胞模型,以确定JP2磷酸化如何调节E-C偶联和切割诱导的JP2NT
发生、核转位和转录调控。在目标2中,我们将使用我们的新JP2 Calain
耐药小鼠与JP2NT过度表达相结合以确定这些靶向途径如何调节
体内心脏对应激的反应。我们将确定E-C如何将结构/功能和心脏基因偶联
这些小鼠在压力超负荷和心肌梗死时,转录会发生变化。我们预计
我们的研究将为调控JP2/JP2NT功能的调控机制提供重要的见解
他们对心脏病发病机制的有益贡献。
英文摘要
PROJECT SUMMARY
Junctophilin 2 (JP2) is an essential structural protein required for the formation of junctional couplings (i.e.,
cardiac dyads) between the transverse (T)-tubule membrane and the sarcoplasmic reticulum (SR). JP2 function
is therefore fundamental for the local control of Ca2+-induced Ca2+ release and efficient contraction in ventricular
myocytes during cardiac excitation-contraction (E-C) coupling. JP2 protein levels progressively decline in failing
human hearts and in animal models of heart failure leading to T-tubule remodeling and loss of E-C coupling
function. The downregulation of JP2 at E-C coupling sites is in part due to specific cleavage by the Ca2+-activated
protease calpain that is implicated in a variety of heart diseases. During the previous funding period, we
demonstrated that stress- and calpain-dependent cleavage of JP2 liberates a novel, nuclear translocating, N-
terminal fragment (JP2NT) that represses maladaptive transcriptional reprogramming in diseased hearts, thus
transducing E-C uncoupling information into a unique cardio-protective excitation-transcription (E-T) coupling
signal to the nucleus. However, how JP2-mediated E-C and E-T coupling phenomena are mechanistically regulated
remains to be determined. Our new preliminary results show that JP2 is reproducibly phosphorylated in stressed
hearts near regions responsible for JP2 cleavage and the subcellular localization of JP2NT. In this competitive
renewal application, we aim to define how stress-induced post-translational modifications regulate the structure,
localization, and function of JP2/JP2NT. We hypothesize that JP2NT-mediated E-T coupling is tightly regulated
by cardiac stress-dependent phosphorylation of JP2 that determines JP2 sensitivity to calpain and JP2NT
nuclear translocation and transcriptional activity. To test our hypothesis, in Aim 1, we will use mutation analysis
and cell models to determine how JP2 phosphorylation regulates E-C coupling and cleavage-induced JP2NT
generation, nuclear translocation and transcriptional regulation. In Aim 2, we will utilize our novel JP2 calpain
resistant mice in combination with JP2NT overexpression to determine how these targeted approaches modulate
cardiac responses to stress in vivo. We will determine how E-C coupling structure/function and cardiac gene
transcription are altered in these mice in response to pressure overload and myocardial infarction. We expect
our studies will provide significant insights into the regulatory mechanisms governing JP2/JP2NT function and
their salutary contribution toward heart disease pathogenesis.
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DOI:
10.1042/bcj20210629
发表时间:
2021-10-15
期刊:
The Biochemical journal
影响因子:
--
作者:
[Wang J, Ciampa G, Zheng D, Shi Q, Chen B, Abel ED, Peng T, Hall DD, Song LS]
通讯作者:
Song LS
DOI:
10.1042/bcj20160606
发表时间:
2016-11-01
期刊:
The Biochemical journal
影响因子:
--
作者:
[Zhong X, Sun B, Vallmitjana A, Mi T, Guo W, Ni M, Wang R, Guo A, Duff HJ, Gillis AM, Song LS, Hove-Madsen L, Benitez R, Chen SR]
通讯作者:
Chen SR
DOI:
10.1007/s00204-019-02405-w
发表时间:
2019-04
期刊:
Archives of toxicology
影响因子:
6.1
作者:
[]
通讯作者:
DOI:
10.1161/circresaha.116.310283
发表时间:
2017-06-09
期刊:
Circulation research
影响因子:
20.1
作者:
[Guo Y, VanDusen NJ, Zhang L, Gu W, Sethi I, Guatimosim S, Ma Q, Jardin BD, Ai Y, Zhang D, Chen B, Guo A, Yuan GC, Song LS, Pu WT]
通讯作者:
Pu WT
DOI:
10.1016/j.jacbts.2018.05.004
发表时间:
2018-08
期刊:
JACC. Basic to translational science
影响因子:
--
作者:
[Wang Y, Chen B, Huang CK, Guo A, Wu J, Zhang X, Chen R, Chen C, Kutschke W, Weiss RM, Boudreau RL, Margulies KB, Hong J, Song LS]
通讯作者:
Song LS
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