Cell-Selective Therapies for Coronary Artery Disease

冠状动脉疾病的细胞选择性疗法

• 批准号: 10543849
• 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
• 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/10543849
• 关键词: Adenovirus Vector; Affect; Animal Model; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Biological; Blood Vessels; Cannulations; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Categories; Cause of Death; 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; Inflammation; Inflammatory Infiltrate; Injury; Interleukin-1 beta; Intervention; Knock-out; Lipids; Messenger RNA; MicroRNAs; Modeling; Mus; Oryctolagus cuniculus; Penetration; Peptides; Pharmaceutical Preparations; 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; cyclin-dependent kinase inhibitor 1B; design; disability; efficacy evaluation; endonuclease; ex vivo perfusion; femoral artery; healing; human tissue; mouse model; nanoparticle; nanoswitch; nanotherapeutic; nanotherapy; novel; novel strategies; overexpression; personalized medicine; pharmacologic; preclinical study; protein expression; recombinant virus; response; restenosis; self assembly; tool; translational potential; treatment strategy; uptake; vascular smooth muscle cell proliferation

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.

动脉粥样硬化性心血管疾病（CVD）是一种严重的疾病，影响着全球数百万人。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。动脉粥样硬化性 CVD 面临的主要治疗挑战之一是提供 针对动脉粥样硬化斑块的治疗，针对有助于其形成的特定细胞，同时 保护内皮。血管内皮细胞提供重要的保护，防止脂质摄取， 炎症和血栓形成。我们假设抑制炎症浸润的细胞选择性疗法 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 对抗心血管疾病和血栓形成。为了实现这一目标，我们将开发一种新颖的 miRNA 开关，它将 具有 miRNA 靶位点的合成修饰 mRNA。作为递送平台，我们将利用阳离子两亲性 细胞穿透肽，与合成 mRNA 混合时形成自组装、压缩的纳米颗粒。 此外，为了增加动脉粥样硬化斑块中炎症的靶向性，我们将结合 miRNA 与靶向 IL1-β 的 siRNA 一起切换，使用相同的阳离子两亲细胞生成纳米颗粒 - 穿透肽。为了实现两个具体目标，我们将测试 1) 这种细胞选择性纳米疗法抑制 经皮介入治疗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 开关纳米疗法在活的、分离的人类冠状动脉中的转化潜力。 目标的完成将为新型生物药的开发奠定基础 可以适应个性化医疗的出现，并将促进心血管疾病的治疗 疾病。