Targeting Pannexin 1 as a Novel Mechanism for Arrhythmia and Fibrosis in Duchenne Cardiomyopathy
靶向 Pannexin 1 作为杜氏心肌病心律失常和纤维化的新机制
基本信息
- 批准号:10543143
- 负责人:
- 金额:$ 14.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-07 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:18 year oldAbbreviationsAblationAgeApoptosisApoptoticArrhythmiaBiologyCa(2+)-Transporting ATPaseCalciumCardiacCardiac Electrophysiologic TechniquesCardiac MyocytesCardiovascular DiseasesCause of DeathCell Membrane PermeabilityCell NucleusCellsCessation of lifeChildhoodCoculture TechniquesComplexCytoplasmDataDedicationsDefectDevelopmentDiagnosisDilated CardiomyopathyDiseaseDuchenne cardiomyopathyDuchenne muscular dystrophyDystrophinFibroblastsFibrosisFoundationsFunctional disorderFundingGene ExpressionGenerationsGenesGeneticGoalsHeart DiseasesHeart failureHistopathologyHomeHumanHypoxiaInflammasomeInflammationInflammatoryInvestigationIonsIsoproterenolKnock-outLinkMeasuresMediatorMentorshipModalityModelingMolecularMorbidity - disease rateMuscle CellsMuscle WeaknessMuscular DystrophiesMyocardial dysfunctionPathologicPathway interactionsPatientsPersonsPhenotypePhysiciansPlayPopulationPrimary Myocardial DiseasesProcessProteinsProton-Translocating ATPasesPurinoceptorRegulationResearchResearch PersonnelRiskRoleRyanodine Receptor Calcium Release ChannelSarcoplasmic ReticulumScientistSignal PathwaySignal TransductionSkeletal MuscleStimulusStretchingStructureSupportive careSymptomsTestingTimeTraining ProgramsTransgenic MiceTransgenic OrganismsVentricularVentricular Arrhythmiaboyscardioprotectioncardiovascular healthcell motilitycell typecoronary fibrosiscurative treatmentsendoplasmexperimental studyextracellulargenetic approachheart functionheart rhythmimprovedin vivoinduced pluripotent stem cellinflammatory modulationmarenostrinmigrationmortalitymouse modelnew therapeutic targetnovelpharmacologicpreservationpreventprogramsrecruitskillssmall moleculetargeted treatmenttranslational studyventilation
项目摘要
PROJECT SUMMARY
Cardiovascular disease is the primary cause of death for patients with Duchenne muscular dystrophy (DMD).
Arrhythmia and cardiac fibrosis leading to dilated cardiomyopathy are the primary mechanisms of cardiac
mortality. Pannexins (Pxs), which are large conductance ion and small molecule channels, have been
implicated in other fibroproliferative diseases and are thought to be arrhythmogenic in other model of cardiac
disease. Loss of dystrophin, the primary defect in DMD, leads to elevated intracellular calcium (Ca2+) which is
also a primary effector of Pxs. The goal of this project is to investigate the mechanisms by which Px1
modulates the development of cardiac fibrosis and arrhythmogenesis in models of DMD cardiomyopathy.
Our preliminary data demonstrate a novel role for Px1 in the development of cardiac fibrosis and inducible
arrhythmia seen in the D2-mdx model of DMD. Genetic ablation of Px1 in the D2-mdx model (mdxPx1-/-)
rescues the cardiac phenotype, including normalization of cardiac fibrosis.as assessed by histopathology and
significant reduction in isoproterenol-induced ventricular ectopy. Based on these data, we hypothesize that
pathologically elevated intracellular Ca2+, a hallmark of this disease, leads to Px1 activation and results in
signaling cascades that activate apoptotic, oxidative, and inflammatory pathways that ultimately lead to
fibroblast activation and the development of cardiac fibrosis. We also hypothesize that Px1 channels represent
an independent mechanism for ventricular arrhythmia via generation of delayed after-depolarizations (DADs).
We with test these hypotheses using the 3 specific aims outlined in this proposal. In Aim 1, we will use
transgenic mice with global Px1 deletion in addition to pharmacological Px inhibition to determine if Px1
activation results in triggered arrhythmia. In Aim 2, we will identify the mechanism by which Px1 contributes to
cardiac fibrosis in DMD cardiomyopathy using pharmacological and genetic strategies. As Pxs are expressed
in both cardiomyocytes and cardiac fibroblasts, Aim 3 will test if fibroblast migration is dependent on Px1
activation in cardiomyocytes and/or fibroblasts using co-culture techniques for human induced pluripotent stem
cell cardiomyocytes (hiPSC-CMs) and cardiac fibroblasts. The completion of these studies will help to improve
our understanding of the mechanisms of cardiovascular disease in DMD and will provide the basis for further
investigation of a novel therapeutic target that has the potential to delay or prevent cardiac mortality in DMD
patients. Additionally, this proposal will allow a promising young physician scientist to gain important skill in
basic and translational studies in cardiac electrophysiology, cell signaling, and inflammation/fibrosis biology
under the expert guidance of a highly accomplished and dedicated mentorship committee. These new skills will
provide the foundation for a successful transition from junior investigator to an independently-funded academic
physician scientist.
项目摘要
心血管疾病是Duchenne肌营养不良(DMD)患者死亡的主要原因。
心律不齐和心脏纤维化导致扩张心肌病是心脏的主要机制
死亡。大电导离子和小分子通道的Pannexins(PXS)已是
与其他纤维增生性疾病有关,被认为是心律不齐的心脏模型
疾病。 DMD的主要缺陷肌营养不良蛋白的丧失导致细胞内钙(Ca2+)升高
也是PX的主要效应子。该项目的目的是研究PX1的机制
调节DMD心肌病模型中心脏纤维化和心律失常的发展。
我们的初步数据证明了PX1在心脏纤维化发展和可诱导的发展中的新作用
在DMD的D2-MDX模型中看到的心律失常。 D2-MDX模型中PX1的遗传消融(MDXPX1 - / - )
营救心脏表型,包括心脏纤维化的归一化。
异丙肾上腺素诱导的心室外系的显着降低。基于这些数据,我们假设
病理上升高的细胞内Ca2+是该疾病的标志,导致PX1激活,并导致
信号传导级联激活凋亡,氧化和炎症途径,最终导致
成纤维细胞激活和心脏纤维化的发展。我们还假设PX1通道代表
通过产生延迟的peLalalization(DADS)的室心律失常的独立机制。
我们使用本提案中概述的3个特定目的进行测试这些假设。在AIM 1中,我们将使用
除药理学PX抑制外,具有全局PX1缺失的转基因小鼠以确定PX1是否是否
激活导致心律不齐。在AIM 2中,我们将确定PX1贡献的机制
使用药理和遗传策略的DMD心肌病中的心脏纤维化。随着PX表示
在心肌细胞和心脏成纤维细胞中,AIM 3将测试成纤维细胞迁移是否取决于PX1
使用共培养技术用于人类诱导的多能茎,在心肌细胞和/或成纤维细胞中激活
细胞心肌细胞(HIPSC-CM)和心脏成纤维细胞。这些研究的完成将有助于改善
我们对DMD中心血管疾病机制的理解,将为进一步提供基础
研究具有延迟或预防DMD心脏死亡率的新型治疗靶标
患者。此外,该建议将允许有前途的年轻医师科学家获得重要的技能
心脏电生理学,细胞信号和炎症/纤维化生物学的基础和翻译研究
在一个高度成就和敬业的指导委员会的专家指导下。这些新技能将
为从初级调查员到独立资助的学术而成功过渡为成功的基础
医师科学家。
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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Frank J Raucci其他文献
Frank J Raucci的其他文献
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{{ truncateString('Frank J Raucci', 18)}}的其他基金
Targeting Pannexin 1 as a Novel Mechanism for Arrhythmia and Fibrosis in Duchenne Cardiomyopathy
靶向 Pannexin 1 作为杜氏心肌病心律失常和纤维化的新机制
- 批准号:
10326854 - 财政年份:2021
- 资助金额:
$ 14.84万 - 项目类别:
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