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MicroRNA Detargeting Novel Therapy for Coronary Artery Disease

MicroRNA 脱靶治疗冠状动脉疾病的新疗法

基本信息

批准号：
8788329
负责人：
Hana Totary-Jain
金额：
$ 24.9万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
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：
2013-10-03 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8788329
关键词：
3&apos 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 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 success vector

项目摘要

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. 项目总结/文摘