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：
9474655
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/9474655
关键词：
Adenovirus Vector Advanced Development Affect Arterial Fatty Streak Atherosclerosis Balloon Angioplasty Blood Vessels Cardiovascular Diseases Cardiovascular system Cause of Death Cell Proliferation Cells Clinical Competence Coronary Arteriosclerosis Cyclin-Dependent Kinase Inhibitor Development Dimensions Endothelial Cells Endothelium Future Generations Growth Human Hyperplasia Impaired wound healing Impairment 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 type clinical practice clinically relevant design efficacy testing healing improved innovation macrophage migration mortality novel novel therapeutic intervention novel therapeutics overexpression percutaneous coronary intervention public health relevance 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）是全球死亡的主要原因。尽管过去二十年来支架治疗方面取得了重大的技术进步，但再狭窄和血栓形成（主要是晚期和很晚）仍然是导致支架相关的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以及严格的不利权衡。毒品洗脱支架（DES）有效地抑制了新的生长，但以不称职的山地为代价，而支架支撑杆覆盖率不佳。这种无法提供细胞选择性治疗阻碍了经皮干预的进展。作为响应，我们开发了一种创新的microRNA（miRNA）基于细胞选择疗法，从而实现了惊人的球囊血管成形术模型。这种新型的治疗选择性地抑制了新的增生和感染，同时促进血管重新皮层化，降低过度凝固性并恢复对与无差异对照无法区分的水平的内皮依赖性血管舒张反应。为了将这种理论策略转化为临床环境，并更好地反映了在介入程序下的患者的状况，我们旨在在建立的动脉粥样硬化模型中测试我们策略的效率。在三个特定目标中，我们将评估这种基于miRNA的细胞选择疗法对（1）抑制动脉粥样硬化的能力。（2）促进动脉粥样硬化；（3）与DES相比，抑制内皮狭窄并恢复内皮覆盖范围。这些研究具有巨大的治疗意义，它们的成功完成将推动细胞选择疗法的发展，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。