MicroRNA Detargeting Novel Therapy for Coronary Artery Disease

MicroRNA 脱靶治疗冠状动脉疾病的新疗法

• 批准号: 8838234
• 负责人: Hana Totary-Jain
• 金额: $ 24.61万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-03 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8838234
• 关键词: 3' Untranslated Regions; Accounting; Acute; Affect; Balloon Angioplasty; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Cause of Death; Cells; Cessation of life; Clinical; Coronary Arteriosclerosis; Data; Development; Development Plans; Endothelial Cells; Ensure; Environment; Gene Expression; Goals; Growth; In Vitro; Incidence; Injury; Knowledge; Maintenance; Medical; Mentors; Messenger RNA; Metals; MicroRNAs; Modeling; Myocardial Infarction; Pharmaceutical Preparations; Phase; Phenotype; Play; Rattus; Regulation; Regulator Genes; Research; Research Project Grants; Risk; Role; Safety; Sensitivity and Specificity; Sirolimus; Stents; Subfamily lentivirinae; Testing; Therapeutic; Training; Translations; United States; Untranslated Regions; Virus; abstracting; angiogenesis; base; career development; implantation; in vivo; in vivo Model; inhibitor/antagonist; innovation; migration; novel; novel strategies; novel therapeutic intervention; novel therapeutics; operation; percutaneous coronary intervention; research study; response to injury; restenosis; skills; stent thrombosis; success; targeted sequencing; targeted treatment; vector

7. Project Summary/Abstract Cardiovascular disease accounts for nearly one third of deaths globally, and Coronary Artery Disease remains the #1 cause of death in the United States. The introduction of the Drug-Eluting Stent (DES) in 2002 revolutionized the field of PCI, by significantly reducing rates of restenosis when compared to bare-metal stents (BMS). Despite the clear clinical advantage of DES, concerns have been raised over their long-term safety, with particular reference to stent thrombosis related to delayed endothelialisation. New therapeutic strategies that can specifically target VSMC and other infiltrated cells but not VEC are needed. MiRNAs act as negative regulators of gene expression by inhibiting the translation or promoting the degradation of target mRNAs. Recent studies show that the mir-143/145 cluster plays important roles in the phenotypic switching of SMC between the quiescent and the proliferative phenotypes. These findings opened the door to potentially novel therapies for restenosis. However, our preliminary data show that increasing the expression of these miRNAs in a non-targeted manner inhibits VEC growth and migration. Therefore, in this application we propose to: 1) Investigate the effect of a mir-143/145 de-targeting strategy on VSMC and VEC proliferation and migration in vitro. 2) Evaluate the specificity and the sensitivity of the de-targeting strategy in a rat carotid artery balloon injury in vivo, and 3) Examine the mir-143/145 de-targeting strategy in the same balloon injury model in vivo. To achieve these aims we will use the endothelial cell specific miRNA to our advantage (mir-126), and we will insert target sequences for mir-126 or random sequences into the 3'-end of a mir-143/mir-145 expressing lentivirus. Infected VSMC and VEC will be tested for proliferation and migration. The same viruses will be will be administered to the rats immediately following balloon injury and the neointimal/media ratio and the integrity of VEC will be assessed. This research plan is meant to be part of a Career Development Plan through which the applicant aims to obtain critical knowledge and technical skills. The extraordinary facilities and the availability of advisors and collaborators ensure an optimal environment for the training period. The mentored phase will therefore allow the transition with success to an independent phase. The applicant will continue to develop the final aims of this research project with the long-term goal to develop novel targeted therapies for the treatment of Coronary Artery Disease.

7。项目摘要/摘要 心血管疾病占全球死亡的近三分之一，冠状动脉疾病 仍然是美国死亡的第一名。 2002年引入药物洗脱支架（DES） 与裸机相比，PCI领域彻底革新了PCI领域 支架（BMS）。尽管DES具有明显的临床优势，但长期的担忧已引起了人们的关注 安全性，特别是指与延迟内皮化有关的支架血栓形成。新治疗 需要专门针对VSMC和其他浸润细胞而不是VEC的策略。 miRNA通过抑制翻译或促进基因表达的负调节剂 目标mRNA的降解。最近的研究表明，miR-143/145簇在 SMC在静止和增殖表型之间的表型切换。这些发现打开了 潜在的新疗法的重新狭窄疗法的门。但是，我们的初步数据表明，增加 这些miRNA以非目标的方式表达抑制VEC的生长和迁移。因此，在此 我们提出的应用：1）研究miR-143/145脱靶策略对VSMC和VEC的影响 体外增殖和迁移。 2）评估脱靶策略的特异性和敏感性 大鼠颈动脉球囊在体内损伤，3）检查MiR-143/145脱靶策略。 体内气球损伤模型。为了实现这些目标，我们将使用内皮细胞特异性miRNA 优势（miR-126），我们将把miR-126或随机序列的目标序列插入A的3'-末端 mir-143/mir-145表达慢病毒。被感染的VSMC和VEC将测试用于增殖和迁移。 气球受伤后，将立即将同样的病毒施用给大鼠 将评估新的/媒体比率和VEC的完整性。 该研究计划旨在成为申请人目标的职业发展计划的一部分 获得关键的知识和技术技能。非凡的设施以及顾问的可用性 合作者确保在培训期间有最佳的环境。因此，指导阶段将允许 成功向独立阶段的过渡。申请人将继续发展 该研究项目具有长期目标，以开发新的靶向疗法来治疗冠状动脉 动脉疾病。