SUMO1 and SERCA2a Function

SUMO1 和 SERCA2a 功能

基本信息

批准号：
8594897
负责人：
Roger J. Hajjar
金额：
$ 40.34万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8594897
关键词：
Acute Address Animal Model Binding Proteins Calcium Calcium ion Cardiac Cardiac Myocytes Cell physiology Cells Chronic Clinical Clinical Trials Complementary DNA Congestive Heart Failure Cytoplasmic Protein DNA Repair DNA biosynthesis Dependovirus Development Devices Enzymes Excision Experimental Models Family Gene Delivery Gene Transfer Genes Genetic Transcription Goals Heart Heart Hypertrophy Heart Transplantation Heart failure Human Hypertrophy Incidence Intervention Lysine Mediating Modeling Molecular Mus Myocardium Nature Pathogenesis Pathway interactions Patients Peptides Performance Phase Physiological Post-Translational Protein Processing Proteins Pump Randomized Regulation Resistance Role SERCA2a Sarcoplasmic Reticulum Site Specificity Testing Therapeutic Therapeutic Effect Transgenic Mice Transplantation Ubiquitin United States Work base constriction enzyme activity gene therapy hemodynamics improved in vivo man mortality mutant novel overexpression phospholamban prevent protein expression protein function protein transport public health relevance research study restoration sarcoplasmic reticulum calcium ATPase sulfoenolpyruvate therapeutic target ubiquitin-protein ligase

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）：尽管药物治疗和新型设备取得了重大进展，但美国充血性心力衰竭的发病率仍在持续增加。因此，迫切需要治疗心力衰竭的新疗法。随着对心力衰竭发病机制的分子机制有了更好的了解，新的靶点正在出现。心力衰竭的一个关键异常是钙离子处理缺陷，这已被证明与心肌细胞肌浆网（SR）功能异常有关。在多种心力衰竭动物模型以及从接受移植的患者移植的衰竭心脏中分离出的心肌细胞中，SERCA2a 的表达和活性降低。恢复 SERCA2a 表达与分离心肌细胞的正性肌力和松弛性改善以及心力衰竭实验模型中心脏功能的改善相关。最近，我们的小组进行了一项首次人体随机基因治疗试验，使用携带 SERCA2a 的腺相关 1 型载体。在这项试验中，我们发现将 AAV1.SERCA2a 递送给晚期心力衰竭患者可改善收缩性心力衰竭患者的整体临床状态，进一步凸显 SERCA2a 作为这种疾病治疗靶点的潜在重要性。我们之前启动临床试验的工作是基于前提是 SERCA2a 总蛋白表达的变化对于心力衰竭中观察到的钙循环异常至关重要。最近，我们发现 SERCA2a 的水平和活性与特定细胞质蛋白 SUMO1（小泛素样修饰剂 1 型）的水平平行调节。人们发现 SUMO 化参与许多细胞过程，例如蛋白质运输、基因转录以及 DNA 复制和修复。我们发现 SERCA2a 和 SUMO1 水平在心力衰竭模型和衰竭的人类心肌中均降低。我们发现，在心力衰竭小鼠模型中，增加 SUMO1 水平可改善血流动力学性能并降低死亡率。我们现在建议进一步表征 SUMO1 调节 SERCA2a 功能的分子机制，并评估调节 SERCA2a SUMO 化的多种途径。