MicroRNA-Based, Cell-Selective Therapy for Coronary Artery Disease

基于 MicroRNA 的冠状动脉疾病细胞选择性疗法

基本信息

批准号：
9110298
负责人：
Hana Totary-Jain
金额：
$ 37.38万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9110298
关键词：
Adenovirus Vector Advanced Development Affect Arterial Fatty Streak Atherosclerosis Balloon Angioplasty Blood Platelets Blood Vessels Cardiovascular Diseases Cardiovascular system Cause of Death Cell Proliferation Cells Clinical Coronary Arteriosclerosis Cyclin-Dependent Kinase Inhibitor Development Employee Strikes Endothelial Cells Endothelium Future Generations Growth Healed Health Human Hyperplasia Impaired wound healing Inflammation Inflammatory Intervention Life Expectancy Metals MicroRNAs Modeling Morbidity - disease rate Necrosis Oryctolagus cuniculus Outcome Patients Peripheral Pharmaceutical Preparations Play Polymers Procedures Process Proliferating Property Publishing Quality of life Rattus Regimen Role Safety Scanning Electron Microscopy Sirolimus Smooth Muscle Myocytes Stents Technology Testing Therapeutic Thrombophilia Thrombosis Translating Vascular Diseases Vascular Smooth Muscle analog atherogenesis base cell motility cell type clinical practice clinically relevant design efficacy testing healing improved innovation macrophage mortality novel novel therapeutic intervention novel therapeutics overexpression percutaneous coronary intervention response restenosis restoration stent thrombosis tool

项目摘要

DESCRIPTION: Cardiovascular disease (CVD) is the leading cause of death worldwide. Despite the major technological advances in stent therapy over the past two decades, restenosis and thrombosis (primarily late and very late) remain principal factors contributing to stent-associated morbidity and mortality rates. To date, stent therapies are non-selective, affecting vascular smooth muscle cells and endothelial cells alike and exacting unfavorable trade-offs. Drug-eluting stents (DES) effectively suppress neointimal growth, but at the expense of poor stent strut coverage with incompetent endothelium. This inability to deliver cell-selective therapy has hindered progress in percutaneous interventions. In response, we have developed an innovative microRNA (miRNA)- based, cell-selective therapy that achieved striking results in an established normal rat model of balloon angioplasty. This novel therapy selectively inhibited neointimal hyperplasia and inflammation while simultaneously promoting vessel reendothelialization, reducing hypercoagulability and restoring the endothelium-dependent vasodilatory response to levels indistinguishable from uninjured control. To translate this therapeutic strategy to a clinical setting, and better reflect the condition of patients that undero interventional procedures, we aim to test the efficacy of our strategy in a rabbit model of established atherosclerosis. In three specific aims, we will evaluate the ability of this miRNA-based, cell-selective therapy to (1) inhibit atherogenesis; (2) promote atheroregression; and (3) inhibit in-stent restenosis and restore endothelial-strut coverage when compared against DES. These studies have tremendous therapeutic implications, and their successful completion will advance the development of cell-selective therapies and significantly impact the clinical practice of cardiovascular intervention to improve the life expectancy of CVD patients.

描述：心血管疾病 (CVD) 是全世界死亡的主要原因，尽管支架治疗在过去二十年中取得了重大技术进步，但再狭窄和血栓形成（主要是晚期和极晚期）仍然是导致支架相关发病率和死亡率的主要因素。迄今为止，支架疗法是非选择性的，会影响血管平滑肌细胞和内皮细胞，并需要对药物洗脱支架（DES）进行不利的权衡。有效抑制新内膜生长，但代价是支架支柱覆盖不良，内皮功能不全，无法提供细胞选择性。治疗阻碍了经皮介入治疗的进展。为此，我们开发了一种基于 microRNA (miRNA) 的创新细胞选择性疗法，该疗法在已建立的正常大鼠球囊血管成形术模型中取得了惊人的结果。同时促进血管再内皮化，降低高凝状态并将内皮依赖性血管舒张反应恢复到与未受伤控制无法区分的水平。将这种治疗策略应用于临床，并更好地反映接受介入手术的患者的状况，我们的目标是在已建立的动脉粥样硬化兔子模型中测试我们的策略的功效，我们将在三个具体目标中评估这种 miRNA 的能力。与 DES 相比，基于细胞的选择性治疗能够 (1) 抑制动脉粥样硬化形成；(2) 促进动脉粥样硬化消退；(3) 抑制支架内再狭窄并恢复内皮支架覆盖。意义及其成功完成将推动细胞选择性疗法的发展，并显着影响心血管干预的临床实践，以提高CVD患者的预期寿命。