SUMO1 and SERCA2a Function

SUMO1 和 SERCA2a 功能

基本信息

项目摘要

DESCRIPTION (provided by applicant):The incidence of congestive heart failure continues to increase in the United States despite significant advances in pharmacological therapy and novel devices. For this reason, there is an urgent need for novel therapies to treat heart failure. With a better understanding of the molecular mechanisms involved in the pathogenesis of heart failure, new targets are emerging. A key abnormality in heart failure is defective handling of calcium ions which has been shown to be related to abnormal sarcoplasmic reticulum (SR) function in cardiac myocytes. Reduced expression and activity of SERCA2a have been shown in multiple animal models of heart failure and in cardiomyocytes isolated from failing hearts explanted from patients undergoing transplantation. Restoring SERCA2a expression is associated with improved inotropy and lusitropy of isolated cardiomyocytes and with improved cardiac function in experimental models of heart failure. More recently, our group carried out a First-in-Man randomized gene therapy trial, using adeno-associated type 1vector carrying SERCA2a. In this trial, we found that AAV1.SERCA2a delivered to patients with advanced heart failure led to an improvement in the overall clinical status of patients with systolic heart failur, further highlighting the potential importance of SERCA2a as a therapeutic target in this condition. Our previous work, which led to the initiation of the clinical trials, was based on the premise that changes in the total protein expression of SERCA2a was critical in the calcium cycling abnormalities observed in heart failure. More recently, we found that the levels and activity of SERCA2a are modulated in parallel with the levels of a specific cytoplasmic protein SUMO1 (small ubiquitin-like modifier type 1). SUMOylation has been found to be involved in many cellular processes such as protein transport, gene transcription and DNA replication and repair. We found that SERCA2a and SUMO1 levels were both reduced in models of heart failure and in failing human myocardium. We showed that increasing SUMO1 levels led to improved hemodynamic performance and reduced mortality in a murine model of HF. We now propose to further characterize the molecular mechanisms of SUMO1 in regulating SERCA2a function and to evaluate the multiple pathways regulating SUMOylation of SERCA2a.
描述(由申请人提供):尽管在药物治疗和新设备方面取得了重大进展,充血性心力衰竭的发病率在美国仍在继续增加。因此,迫切需要新的治疗方法来治疗心力衰竭。 随着对心力衰竭发病机制分子机制的进一步了解,新的靶点不断涌现。心力衰竭的一个关键异常是钙离子的处理缺陷,这已被证明与心肌细胞肌浆网(SR)功能异常有关。SERCA2a的表达和活性在多种心力衰竭动物模型中以及从移植患者的衰竭心脏中分离出来的心肌细胞中都显示出降低。在心力衰竭的实验模型中,恢复SERCA2a的表达与改善分离的心肌细胞的正性和正性以及改善心功能有关。最近,我们小组进行了一项首例人类随机基因治疗试验,使用携带SERCA2a的腺相关1型载体。在这项试验中,我们发现,向晚期心力衰竭患者提供AAV1.SERCA2a导致了收缩性心力衰竭患者的总体临床状况的改善,进一步强调了SERCA2a作为这种疾病的治疗靶点的潜在重要性。我们之前的工作,导致了临床试验的启动,是基于 前提是SERCA2a总蛋白表达的变化在心力衰竭观察到的钙循环异常中起关键作用。最近,我们发现SERCA2a的水平和活性与一种特定的细胞质蛋白SUMO1(小泛素样修饰物类型1)的水平是平行调节的。已发现苏莫化参与许多细胞过程,如蛋白质转运、基因转录和DNA复制与修复。我们发现,在心力衰竭模型和衰竭的人类心肌中,SERCA2a和SUMO1水平都降低了。我们发现,在心力衰竭小鼠模型中,增加SUMO1水平可以改善血流动力学性能,降低死亡率。我们现在建议进一步研究SUMO1调节SERCA2a功能的分子机制,并评估调节SERCA2a SUMO化的多个途径。

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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Roger J. Hajjar其他文献

Structure-Based Design of Phospholamban Mutants for Gene Therapy
  • DOI:
    10.1016/j.bpj.2009.12.4188
  • 发表时间:
    2010-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Simon J. Gruber;Kim N. Ha;Elizabeth L. Lockamy;Razvan L. Cornea;Roger J. Hajjar;Gianluigi Veglia;David D. Thomas
  • 通讯作者:
    David D. Thomas
1042. Tracking and Gene Expression Profile of Bone Marrow Mesenchymal Stem Cells Injected into Pig Myocardium by Magnetic Resonance Imaging and Laser-Capture Microdissection
  • DOI:
    10.1016/j.ymthe.2006.08.1138
  • 发表时间:
    2006-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Elie R. Chemaly;Irina Pomerantseva;Ryuichi Yoneyama;Djamel Lebeche;Davide Gianni;Kozo Hoshino;Yoshiaki Kawase;Federica del Monte;Roger J. Hajjar
  • 通讯作者:
    Roger J. Hajjar
AAV delivery strategy with mechanical support for safe and efficacious cardiac gene transfer in swine
具有机械支持的腺相关病毒递送策略用于猪的安全有效心脏基因转移
  • DOI:
    10.1038/s41467-024-54635-x
  • 发表时间:
    2024-12-01
  • 期刊:
  • 影响因子:
    15.700
  • 作者:
    Renata Mazurek;Serena Tharakan;Spyros A. Mavropoulos;Deanndria T. Singleton;Olympia Bikou;Tomoki Sakata;Taro Kariya;Kelly Yamada;Erik Kohlbrenner;Lifan Liang;Anjali J. Ravichandran;Shin Watanabe;Roger J. Hajjar;Kiyotake Ishikawa
  • 通讯作者:
    Kiyotake Ishikawa
Therapeutic Targeted Delivery of AAV9 Sh BNIP3 Reverses Cardiac Remodeling and Improves Diastolic and Systolic Function in a Rat Model of Pressure Overload Induced Heart Failure
  • DOI:
    10.1016/j.cardfail.2012.06.106
  • 发表时间:
    2012-08-01
  • 期刊:
  • 影响因子:
  • 作者:
    Antoine H. Chaanine;Ronald E. Gordon;Ludovic Benard;Erik Kohlbrenner;Roger J. Hajjar
  • 通讯作者:
    Roger J. Hajjar
Spectroscopic Design of Phospholamban Mutants to Treat Heart Failure
  • DOI:
    10.1016/j.bpj.2009.12.1337
  • 发表时间:
    2010-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Simon J. Gruber;Suzanne Haydon;Kim N. Ha;Roger J. Hajjar;Gianluigi Veglia;David D. Thomas
  • 通讯作者:
    David D. Thomas

Roger J. Hajjar的其他文献

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{{ truncateString('Roger J. Hajjar', 18)}}的其他基金

Small Molecule Therapy for the Treatment of Heart Failure
治疗心力衰竭的小分子疗法
  • 批准号:
    9335758
  • 财政年份:
    2017
  • 资助金额:
    $ 42.38万
  • 项目类别:
Anti-AAV Antibodies as an Obstacle to Cardiac AAV Gene Therapy
抗 AAV 抗体是心脏 AAV 基因治疗的障碍
  • 批准号:
    9281067
  • 财政年份:
    2016
  • 资助金额:
    $ 42.38万
  • 项目类别:
Anti-AAV Antibodies as an Obstacle to Cardiac AAV Gene Therapy
抗 AAV 抗体是心脏 AAV 基因治疗的障碍
  • 批准号:
    9176405
  • 财政年份:
    2016
  • 资助金额:
    $ 42.38万
  • 项目类别:
Role of miR25 in Heart Failure
miR25 在心力衰竭中的作用
  • 批准号:
    9249966
  • 财政年份:
    2015
  • 资助金额:
    $ 42.38万
  • 项目类别:
Role of miR25 in Heart Failure
miR25 在心力衰竭中的作用
  • 批准号:
    8914275
  • 财政年份:
    2015
  • 资助金额:
    $ 42.38万
  • 项目类别:
Treating Ventricle and Valve: New Synergies for Ischemic LV Remodeling with MR
治疗心室和瓣膜:MR 缺血性左室重塑的新协同作用
  • 批准号:
    9195751
  • 财政年份:
    2015
  • 资助金额:
    $ 42.38万
  • 项目类别:
Calcium Pump Activators for Heart Failure Therapy
用于心力衰竭治疗的钙泵激活剂
  • 批准号:
    9268662
  • 财政年份:
    2015
  • 资助金额:
    $ 42.38万
  • 项目类别:
Calcium Pump Activators for Heart Failure Therapy
用于心力衰竭治疗的钙泵激活剂
  • 批准号:
    9096874
  • 财政年份:
    2015
  • 资助金额:
    $ 42.38万
  • 项目类别:
SUMO1 and SERCA2a Function
SUMO1 和 SERCA2a 功能
  • 批准号:
    8594897
  • 财政年份:
    2013
  • 资助金额:
    $ 42.38万
  • 项目类别:
SUMO1 and SERCA2a Function
SUMO1 和 SERCA2a 功能
  • 批准号:
    8725733
  • 财政年份:
    2013
  • 资助金额:
    $ 42.38万
  • 项目类别:

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