Mechanisms and Therapeutic Role of C-terminus of Cav1.3 L-type Calcium Channel in the Heart
Mechanisms and Therapeutic Role of C-terminus of Cav1.3 L-type Calcium Channel in the Heart
批准号:
10481142
负责人:
Mohamed Boutjdir
金额:
$0.0万
依托单位国家:
美国
项目类别:
财政年份:
2013
资助国家:
美国
项目状态:
未结题
起止时间:
2013-10-01 至 2026-03-31
关键词:
Action PotentialsAdultAgingAnterior Descending Coronary ArteryBiochemicalCalciumCardiacCardiac MyocytesCardiac developmentCardiovascular DiseasesCause of DeathCell NucleusCell membraneCell physiologyChIP-seqCouplingDataDeveloped CountriesDevelopmentEchocardiographyElectrophysiology (science)ElementsEnhancersEnvironmentFDA approvedGene ExpressionGene Expression RegulationGenesGenetic TranscriptionHealthHeartHeart AtriumHeart ContractilitiesHeart failureHistologyIonsKnockout MiceL-Type Calcium ChannelsLaboratoriesLeftLeft Ventricular Ejection FractionLeft Ventricular FunctionLigationLightMediatingMessenger RNAMusMuscle CellsNeonatalNeurosecretory SystemsOpticsPatientsPeptidesPlayPopulationPromoter RegionsPropertyProteinsPublic HealthPublishingRegulationReportingResearchRoleSignal TransductionSinoatrial NodeTestingTherapeuticTimeTissuesVentricularVeteransWestern BlottingWorkatrioventricular nodedensitydesigndesign and constructiondifferential expressionfetalfunctional restorationgene therapyheart functionimprovedin vivoinnovationmouse modelnovelnovel therapeutic interventionpatch clamppromoterrational designtranscription factortranscriptome sequencingtranslational impactvectorvoltage
中文摘要
在心脏中,l型钙通道有两种,经典的Cav1.2型和新颖的Cav1.2型
英文摘要
In the heart, there are two types of L-type calcium channels, the classical Cav1.2 and the novel
less characterized Cav1.3. They both convert cell-membrane depolarization into calcium
transients and initiate excitation-contraction coupling. Interestingly, Cav1.3 is expressed in the
supraventricular tissue and ventricles of the fetal and neonatal hearts but not in the ventricles of
the adult heart. Cav1.3 also has an extended C-terminus. Relevant to this application is that our
preliminary data demonstrate that the C-terminus of Cav1.3 is mobile and functions as a
transcription auto-enhancer of its own Cav1.3 gene. This unique endogenous property can be
leveraged to generate inotropic force necessary to restore cardiac function in the setting of heart
failure which is highly prevalent in Veterans. Here we will test, for the first time, the hypothesis
that the translocation of the Cav1.3 C-terminus mobile fragment to the nucleus will upregulate
Cav1.3 gene expression at specific promoter region(s) and thus provide additional calcium entry
into the cardiac myocyte resulting in improved cardiac function in a murine model of heart
failure. This hypothesis will be tested in three aims: Aim 1: Investigate the regulation of gene
expression by C-terminus of Cav1.3 in a native environment; Aim 2: Determine the mechanisms
of Cav1.3 C-terminus regulation of Cav1.3 gene promoter activity; Aim 3: Investigate the
potential therapeutic impact of Cav1.3 C-terminus in heart failure. Studies will be carried out by
a combination of electrophysiological (patch-clamp and optical mapping), RNA-seq,
biochemical, echocardiography and histology, in in-vivo and ex-vivo hearts. The findings from
this work will provide a novel mechanism by which Cav1.3 L-type calcium channel acts not only
as a conventional ion pore but also as a transcription factor regulating gene expression and cell
function via its C-terminus. The ability of the C-terminus of Cav1.3 to upregulate its own gene
can be exploited for the development of novel inotropic therapies for heart failure which is
prevalent in Veterans.
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