Cell-Selective Therapies for Coronary Artery Disease

冠状动脉疾病的细胞选择性疗法

基本信息

批准号：
10323294
负责人：
Hana Totary-Jain
金额：
$ 48.6万
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 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10323294
关键词：
Adenovirus Vector Affect Animal Model Apolipoprotein E Arterial Fatty Streak Atherosclerosis Biological Blood Vessels Cardiovascular Diseases Cardiovascular system Carotid Arteries Categories Cations Cause of Death Cell Proliferation Cell physiology Cells Cessation of life Clinical Clinical Research Coronary Arteriosclerosis Coronary artery Cyclin-Dependent Kinase Inhibitor Development Endothelial Cells Endothelium Epidemic Event Exhibits Foundations Functional disorder Goals Heart Human Hyperplasia Incidence Infection Infiltration Inflammation Inflammatory Injury Interleukin-1 beta Intervention Knock-out Lipids Messenger RNA MicroRNAs Modeling Mus Oryctolagus cuniculus Peptides Pharmaceutical Preparations Pharmacology Physiology Proteins Rattus Recurrence Regional Perfusion Resistance Safety Site Small Interfering RNA Smooth Muscle Myocytes Technology Testing Therapeutic Thrombophilia Thrombosis Time Toxic effect Translating Untranslated Regions Vascular Endothelial Cell Vascular Smooth Muscle Venous base design disability endonuclease ex vivo perfusion femoral artery healing human tissue mouse model nanoparticle nanotherapeutic nanotherapy novel novel strategies overexpression personalized medicine preclinical study protein expression recombinant virus response restenosis tool translational potential treatment strategy uptake vascular smooth muscle cell proliferation

项目摘要

Atherosclerotic cardiovascular disease (CVD) represents a serious affliction affecting millions globally. Despite recent advances in pharmacological and percutaneous interventions, CVD remains the leading cause of death and disability in the world. One of the main therapeutic challenges facing atherosclerotic CVD is the delivery of therapies to the atherosclerotic plaque that target the specific cells which contribute to its formation, while protecting the endothelium. Vascular endothelial cells provide crucial protection against lipid uptake, inflammation and thrombosis. We hypothesize that cell-selective therapy that inhibits infiltration of inflammatory cells and proliferation of vascular smooth muscle cells, while protecting endothelia cell function will be effective in combating CVD and thrombosis. To achieve this goal, we will develop a novel miRNA switch that combines synthetically modified mRNA with miRNA target site. As a delivery platform we will utilize the cationic amphipathic cell-penetrating peptide that forms a self-assembled, compacted, nanoparticle when mixed with synthetic mRNA. Moreover, to increase the targeting of inflammation in the atherosclerotic plaque, we will combine the miRNA switch together with siRNA targeting IL1-β to generate nanoparticles using the same cationic amphipathic cell- penetrating peptide. In two specific aims, we will test 1) the efficacy of this cell-selective nanotherapy to inhibit atherosclerosis and restenosis after percutaneous intervention, while protecting EC to reduce thrombosis; and 2) the translational potential of the miRNA switch nanotherapy in viable, isolated human coronary arteries. Completion of the aims will provide the foundation for the development of a novel category of biological drugs that can accommodate the advent of personalized medicine and will advance the treatment of cardiovascular disease.

动脉粥样硬化心血管疾病（CVD）代表了一种严重的情感，影响了全球数百万。尽管药物和经皮干预的最新进展，CVD仍然是死亡的主要原因和世界上的残疾。动脉粥样硬化CVD面临的主要治疗挑战之一是交付对动脉粥样硬化斑块的疗法，该斑块靶向有助于其形成的特定细胞，而保护原始植物。血管上的植物细胞提供至关重要的保护，以防止脂质摄取，炎症和血栓形成。我们假设这种细胞选择疗法抑制炎症的浸润细胞和血管平滑肌细胞的增殖，同时保护内皮细胞功能将有效在对抗CVD和血栓形成时。为了实现这一目标，我们将开发一个组合的新型miRNA开关用miRNA靶位点合成修饰的mRNA。作为送货平台，我们将利用阳离子的两亲性与合成mRNA混合时，细胞穿透肽形成自组装，压实的纳米颗粒。此外，要增加动脉粥样硬化斑块中炎症的靶向，我们将结合miRNA 与靶向IL1-β的siRNA一起使用相同的阳离子两亲细胞生成纳米颗粒穿透胡椒。在两个具体目标中，我们将测试1）这种细胞选择性纳米疗法的效率经皮干预后动脉粥样硬化和再狭窄，同时保护EC减少血栓形成；和 2）miRNA开关纳米疗法在可行的，分离的人类冠状动脉中的翻译潜力。目的的完成将为开发新型生物药物的发展提供基础这可以适应个性化药物的进步，并将进步心血管治疗疾病。