Targeting Protein Trafficking in Arrhythmogenic Cardiomyopathy
致心律失常性心肌病中的靶向蛋白质运输
基本信息
- 批准号:10703399
- 负责人:
- 金额:$ 17.93万
- 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:2021-09-15 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:ActinsAddressAffectAgeAnimal ModelArrhythmiaBiologyBirthCardiac MyocytesCardiovascular DiseasesCardiovascular systemCell Culture TechniquesCell modelCessation of lifeCicatrixCo-ImmunoprecipitationsConfocal MicroscopyConnexin 43ConnexinsCoronaryCouplingDataDefectDefibrillatorsDesmosomesDevicesDiseaseDisease modelDoctor of PhilosophyEchocardiographyEducational workshopElectron MicroscopyGap JunctionsGoalsHeartHeart DiseasesHela CellsIntercalated discInternationalIon ChannelIschemiaKnock-outKnowledgeLaboratoriesLigationLinkLocationMediatingMentorsMetabolicMitochondriaModelingMolecularMonitorMusMutant Strains MiceMutationMyocardialMyocardial dysfunctionNamesNormal Statistical DistributionOutcomeOxygenPathologicPatientsPersonsPhenotypePhysical activityPhysiciansPreventionProtein IsoformsProteinsRecoveryRegulationReproducibilityResearchResearch PersonnelResolutionRobin birdRoleScientistSignal TransductionSudden DeathTargeted ResearchTechniquesTelemetryTestingTrainingTraining ProgramsTransfectionTranslatingTranslational ResearchUnited StatesUnited States National Institutes of HealthUniversitiesUtahVirusVocational GuidanceWorkarrhythmogenic cardiomyopathycardioprotectioncareer developmentdesmoglein 2effective therapyexperienceimplantationimprovedin vivoinsightknock-downmedical schoolsmutantnew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticspreservationpreventprofessorprotein transportsudden cardiac deathsymposiumtargeted treatmenttrafficking
项目摘要
ABSTRACT
This proposal is to support the career development of Joseph Palatinus, MD, PhD, to become an
independent physician scientist with a focus on basic/translational research by targeting
protein trafficking as a means to prevent and treat arrhythmias and sudden cardiac death
(SCD). The PI will have as a primary mentor Professor Robin Shaw, MD PhD, who is world
renowned expert in protein trafficking and cardiomyocyte biology. The comprehensive training
program is composed of laboratory-based research, coursework, workshops, grantsmanship
seminars, scientific conferences (local and international), and career guidance by a mentoring
committee. The committee includes the mentors and leverages the combined experience and
technical knowledge of 5 leading independent cardiovascular investigators at the Eccles
Cardiovascular Research and Training Institute at the University of Utah as well as Dr. Jeffery
Saffitz at Harvard Medical School, a world expert on Arrhythmogenic cardiomyopathy. The
research proposed will apply the alternatively translated isoform of Connexin 43 (Cx43),
dubbed GJA1-20k (and an established actin stabilizing protein), to the Desmoglein 2 (DSG2)
mutant model of ACM. Preliminary data has demonstrated disrupted actin organization in both
cellular and animal models of a DSG2 mutation which, in the heart is associated with a loss of
gap junction trafficking to the intercalated disk and downstream cardiac dysfunction. It is
hypothesized that GJA1-20k will lead to recovery of gap junction localization, suppression of
arrhythmias and prevention of SCD in the DSG2 mutant model of ACM by directly interacting
with and stabilizing cellular actin. Two specific aims are proposed: 1) Is actin dysregulation
responsible for the trafficking defects observed in the DSG2 mutant model? And 2) Does GJA1-
20k rescue the cardiomyopathic and arrhythmogenic phenotype of ACM and prevent SCD? High
resolution confocal microscopy, proximity ligation immunolabeling, electron microscopy, co-
immunoprecipitation, echocardiography, and in vivo telemetry monitoring are some of the
advanced techniques which will be used to develop a mechanistic understanding of actin
dependent trafficking mediated by GJA1-20k. The results from this study are expected to
develop a novel paradigm to treat and prevent arrhythmogenic SCD by targeting protein
trafficking.
摘要
这项提议是为了支持约瑟夫·帕拉蒂纳斯的职业发展,医学博士,博士,成为一名
独立的内科科学家,专注于基础/翻译研究
蛋白质转运作为预防和治疗心律失常和心脏性猝死的手段
(SCD)。国际象棋将由世界知名的医学博士罗宾·肖教授担任主要导师
著名的蛋白质运输和心肌细胞生物学专家。综合训练
课程包括基于实验室的研究、课程、工作坊、资质
研讨会、科学会议(本地和国际),以及由导师提供职业指导
委员会审议阶段。该委员会包括导师,并利用综合经验和
ECCLES的5位领先的独立心血管研究人员的技术知识
犹他大学心血管研究和培训研究所以及杰弗里博士
哈佛医学院的萨菲兹说,他是致心律失常心肌病的世界专家。这个
建议的研究将应用连接蛋白43(Cx43)的替代翻译异构体,
被命名为GJA1-20k(和一个已建立的肌动蛋白稳定蛋白),与桥粒蛋白2(DSG2)
ACM的突变模型。初步数据显示,在这两种情况下,肌动蛋白的组织都受到了破坏
DSG2突变的细胞和动物模型,该突变在心脏中与
缝隙连接转运至间盘和下游心功能不全。它是
假设GJA1-20k将导致缝隙连接局部化的恢复,抑制
DSG2基因突变ACM模型的心律失常及SCD的预防
并稳定细胞肌动蛋白。提出了两个具体的目标:1)肌动蛋白是否失调
对在DSG2突变模型中观察到的贩运缺陷负责?2)GJA1是否-
20K挽救ACM的心肌病和致心律失常表型,预防SCD?高
分辨率共聚焦显微镜,邻近连接免疫标记,电子显微镜,共聚焦显微镜
免疫沉淀、超声心动图和活体遥测监测是其中的一部分
先进的技术将被用来发展对肌动蛋白的机械性理解
由GJA1-20K调解的依赖贩运。这项研究的结果预计将
开发靶向蛋白质治疗和预防致心律失常的SCD的新范式
贩卖人口。
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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Joseph A. Palatinus其他文献
Extracorporeal Membrane Oxygenation Support for Hypokalemia-induced Cardiac Arrest: A Case Report and Review of the Literature
- DOI:
10.1016/j.jemermed.2015.02.046 - 发表时间:
2015-08-01 - 期刊:
- 影响因子:
- 作者:
Joseph A. Palatinus;Sarah B. Lieber;Katherine E. Joyce;Jeremy B. Richards - 通讯作者:
Jeremy B. Richards
Prognostic value of point-of-care ultrasound during cardiac arrest: a systematic review
- DOI:
10.1186/s12947-020-0185-8 - 发表时间:
2020-01-13 - 期刊:
- 影响因子:1.600
- 作者:
Ilan Kedan;William Ciozda;Joseph A. Palatinus;Helen N. Palatinus;Asher Kimchi - 通讯作者:
Asher Kimchi
Translating Basic Research on Cx43 Gap Junctions into Therapies for Reducing Scarring and Cardiac Arrhythmia
将 Cx43 间隙连接的基础研究转化为减少疤痕和心律失常的疗法
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:0
- 作者:
R. Gourdie;J. M. Rhett;Emily L. Ongstad;Joseph A. Palatinus;Michael P. O’Quinn - 通讯作者:
Michael P. O’Quinn
Abstract 9561: Connexin43 Interacts with Voltage-Gated Sodium Channel 1.5 in the Perinexus
摘要 9561:Connexin43 与 Perinexus 中的电压门控钠通道 1.5 相互作用
- DOI:
10.1161/circ.124.suppl_21.a9561 - 发表时间:
2011 - 期刊:
- 影响因子:37.8
- 作者:
J. M. Rhett;Joseph A. Palatinus;J. Jourdan;R. Gourdie - 通讯作者:
R. Gourdie
Targeting the Cx43 Carboxyl Terminal H2 Domain Preserves Left Ventricular Function Following Ischemia-Reperfusion Injury
靶向 Cx43 羧基末端 H2 结构域可在缺血再灌注损伤后保留左心室功能
- DOI:
10.1101/668509 - 发表时间:
2019 - 期刊:
- 影响因子:0
- 作者:
Jingbo Jiang;Joseph A. Palatinus;Huamei He;Jegan Iyyathurai;L. Jourdan;Daniel T. Hoagland;G. Bultynck;Zhen Wang;Zhiwei Zhang;K. Schey;S. Poelzing;F. McGowan;R. Gourdie - 通讯作者:
R. Gourdie
Joseph A. Palatinus的其他文献
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{{ truncateString('Joseph A. Palatinus', 18)}}的其他基金
Targeting Protein Trafficking in Arrhythmogenic Cardiomyopathy
致心律失常性心肌病中的靶向蛋白质运输
- 批准号:
10301665 - 财政年份:2021
- 资助金额:
$ 17.93万 - 项目类别:
Connexin 43 gap junction dynamics in the diabetic heart
糖尿病心脏中的连接蛋白 43 间隙连接动态
- 批准号:
7615813 - 财政年份:2009
- 资助金额:
$ 17.93万 - 项目类别:
Connexin 43 gap junction dynamics in the diabetic heart
糖尿病心脏中的连接蛋白 43 间隙连接动态
- 批准号:
8220750 - 财政年份:2009
- 资助金额:
$ 17.93万 - 项目类别:
Connexin 43 gap junction dynamics in the diabetic heart
糖尿病心脏中的连接蛋白 43 间隙连接动态
- 批准号:
8012855 - 财政年份:2009
- 资助金额:
$ 17.93万 - 项目类别:
Connexin 43 gap junction dynamics in the diabetic heart
糖尿病心脏中的连接蛋白 43 间隙连接动态
- 批准号:
8429502 - 财政年份:2009
- 资助金额:
$ 17.93万 - 项目类别:
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