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: 8306029
• 负责人: Hana Totary-Jain
• 金额: $ 13.38万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8306029
• 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; Thrombosis; Training; Translations; United States; Untranslated Regions; Virus; 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; success; vector

DESCRIPTION (provided by applicant): 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 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.

描述（由申请人提供）：心血管疾病占全球死亡人数的近三分之一，冠状动脉疾病仍然是美国的头号死因。2002年药物洗脱支架（DES）的引入彻底改变了PCI领域，与裸金属支架（BMS）相比，药物洗脱支架显著降低了再狭窄率。尽管DES具有明显的临床优势，但人们对其长期安全性提出了担忧，特别是与延迟内皮化相关的支架血栓形成。需要能够特异性靶向VSMC和其他浸润细胞而不是VEC的新的治疗策略。 miRNAs通过抑制靶mRNA的翻译或促进靶mRNA的降解而作为基因表达的负调控因子。最近的研究表明，mir-143/145簇在SMC的表型转换中起着重要的作用。这些发现为再狭窄的潜在新疗法打开了大门。然而，我们的初步数据表明，以非靶向方式增加这些miRNA的表达抑制了VEC的生长和迁移。因此，在本申请中，我们提出：1）研究mir-143/145去靶向策略对体外VSMC和VEC增殖和迁移的影响。2)在体内大鼠颈动脉球囊损伤中评估去靶向策略的特异性和灵敏度，以及3）在体内相同球囊损伤模型中检查mir-143/145去靶向策略。为了实现这些目标，我们将使用对我们有利的内皮细胞特异性miRNA（mir-126），并且我们将mir-126的靶序列或随机序列插入表达mir-143/mir-145的慢病毒的3 '端。将检测受感染的VSMC和VEC的增殖和迁移。球囊损伤后立即对大鼠给予相同的病毒，并评估新生内膜/中膜比率和VEC的完整性。 该研究计划是职业发展计划的一部分，申请人旨在通过该计划获得关键知识和技术技能。非凡的设施和顾问和合作者的可用性确保了培训期间的最佳环境。因此，辅导阶段将使成功过渡到独立阶段。申请人将继续制定本研究项目的最终目标，长期目标是开发用于治疗冠状动脉疾病的新型靶向疗法。