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

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 这项建议是为了支持约瑟夫Palatinus,医学博士,博士的职业发展,成为一个 独立的医生科学家,专注于基础/转化研究, 蛋白质运输作为预防和治疗心律失常和心源性猝死的手段 (SCD)。PI将有一个主要的导师教授罗宾肖,医学博士,谁是世界 著名的蛋白质运输和心肌细胞生物学专家。综合训练 计划是由实验室为基础的研究,课程,研讨会,granitarian 研讨会、科学会议(当地和国际),以及由导师提供的职业指导 以马克思委员会包括导师,并利用他们的综合经验, Eccles 5位领先的独立心血管研究者的技术知识 犹他州大学心血管研究和训练所的Jeffery博士 Saffitz是哈佛医学院的一位心律失常性心肌病专家。的 提出的研究将应用连接蛋白43(Cx43)的替代翻译同种型, 被称为GJA 1 - 20 k(和一种已建立的肌动蛋白稳定蛋白)的桥粒芯糖蛋白2(DSG 2) ACM的突变模型。初步数据表明,在这两种细胞中, DSG 2突变的细胞和动物模型,在心脏中与心脏功能丧失相关, 间隙连接运输到闰盘和下游心脏功能障碍。是 假设GJA 1 - 20 k将导致间隙连接定位的恢复, 在ACM的DSG 2突变模型中通过直接相互作用预防心律失常和SCD 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 负责DSG 2突变模型中观察到的运输缺陷?和2)GJA 1- 20 k拯救ACM的心肌病和致炎表型并预防SCD?高 分辨率共聚焦显微镜,邻位连接免疫标记,电子显微镜,共- 免疫沉淀、超声心动图和体内遥测监测是一些 先进的技术,将用于发展肌动蛋白的机械理解 由GJA 1 - 20 k介导的依赖性贩运。这项研究的结果预计将 通过靶向蛋白质开发治疗和预防致瘤性SCD的新模式 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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

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

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 17.93万
  • 项目类别:
    Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 17.93万
  • 项目类别:
    Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 17.93万
  • 项目类别:
    Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 17.93万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 17.93万
  • 项目类别:
    Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 17.93万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 17.93万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 17.93万
  • 项目类别:
    EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 17.93万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 17.93万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了