SUMO1 and SERCA2a Function

SUMO1 和 SERCA2a 功能

• 批准号: 9087310
• 负责人: Roger J. Hajjar
• 金额: $ 42.38万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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/9087310
• 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; Gene therapy trial; Genes; Genetic Transcription; Goals; Health; 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; hemodynamics; improved; in vivo; man; mortality; mouse model; mutant; novel; novel therapeutics; overexpression; phospholamban; prevent; protein expression; protein function; protein transport; research study; restoration; sarcoplasmic reticulum calcium ATPase; sulfoenolpyruvate; therapeutic target; ubiquitin-protein ligase

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型器械方面取得了重大进展，但美国充血性心力衰竭的发病率仍在继续增加。因此，迫切需要新的治疗心力衰竭的方法。