Cell-Selective Therapies for Coronary Artery Disease

动脉粥样硬化性心血管疾病(CVD)是影响全球数百万人的一种严重疾病。尽管 药物和经皮介入治疗的最新进展，心血管疾病仍然是导致死亡的主要原因 世界上最大的残疾。动脉粥样硬化性心血管疾病面临的主要治疗挑战之一是 针对动脉粥样硬化斑块形成的特定细胞的治疗方法，而 保护血管内皮。血管内皮细胞对脂质摄取提供了至关重要的保护， 炎症和血栓形成。我们假设抑制炎性细胞渗透的细胞选择性疗法 细胞和血管平滑肌细胞的增殖，同时保护内皮细胞的功能将是有效的 在对抗心血管疾病和血栓形成方面。为了实现这一目标，我们将开发一种新型的miRNA开关，它结合了 以miRNA为靶点的合成修饰的mRNA。作为传递平台，我们将利用阳离子两亲性 当与合成的信使核糖核酸混合时，形成一种自组装、致密的纳米颗粒的穿透性多肽。 此外，为了增加对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的小干扰RNA一起切换，使用相同的阳离子两亲性细胞产生纳米颗粒- 穿透肽。在两个特定的目标中，我们将测试1)这种细胞选择性纳米疗法的有效性，以抑制 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开关纳米疗法在可存活的、分离的人类冠状动脉中的翻译潜力。 这些目标的完成将为开发一类新的生物药物奠定基础 这可以适应个性化医学的到来，并将推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.