Cell-Selective Therapies for Coronary Artery 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 随着药物和经皮介入治疗的最新进展，CVD仍然是死亡的主要原因 和残疾的人。动脉粥样硬化性CVD面临的主要治疗挑战之一是递送 靶向有助于其形成的特定细胞的动脉粥样硬化斑块的治疗， 保护内皮细胞。血管内皮细胞对脂质摄取提供重要的保护， 炎症和血栓形成。我们假设，抑制炎性细胞浸润的细胞选择性治疗， 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，我们将开发一种新的miRNA开关， 具有miRNA靶位点的合成修饰的mRNA。作为一个交付平台，我们将利用阳离子两亲 细胞穿透肽，当与合成mRNA混合时，形成自组装、压实的纳米颗粒。 此外，为了增加动脉粥样硬化斑块中炎症的靶向性，我们将联合收割机 与靶向IL 1-β的siRNA一起转换，以使用相同的阳离子两亲性细胞- 穿透肽在两个具体目标中，我们将测试1）这种细胞选择性纳米疗法抑制 动脉粥样硬化和经皮介入后再狭窄，同时保护EC以减少血栓形成;以及 2)miRNA开关纳米疗法在存活的、分离的人类冠状动脉中的翻译潜力。 这一目标的实现将为开发新型生物药物奠定基础 它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

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.