Targeting the Caveolae-Dependent Mechanism of Calcifying Extracellular Vesicle Formation

项目摘要 血管钙化是心血管疾病发病率最重要的预测因子， 慢性肾脏病患者。这些患者广泛的动脉矿物质破坏了血管功能 增加心脏的后负荷目前还没有治疗策略来预防或治疗血管 钙化对矿物质形成的不完全理解阻碍了治疗学的发展 过程血管壁中的钙矿物质形成始于细胞外囊泡（EV）， 钙离子和磷酸根离子之间的相互作用。已发表的数据表明，钙化EV的形成需要 小窝蛋白-1的存在，其是被称为小窝的质膜内陷的结构组分。 然而，小窝可能启动钙化EV形成的机制仍不清楚。的 一项拟议的研究试图追踪钙化EV的形成，以追溯血管平滑肌内的小窝 细胞我们假设小窝进入细胞启动了钙化EV的形成， 矿化潜力的新生囊泡。我们将研究表皮生长因子受体（EGFR）在肿瘤发生发展中的作用 作为小窝蛋白-1相互作用物和钙化EV形成的潜在新介质。研究目的1探索 通过EV形成和促进矿化的小窝依赖机制。我们将分析 随着体内和体外矿化的进展，钙化EV的演变。目标2将测试治疗 改变小窝运输和钙化EV形成以治疗血管性疾病的临床相关策略的潜力 钙化

PROJECT SUMMARY Vascular calcification is the most significant predictor of cardiovascular morbidity and is especially prevalent in individuals with chronic kidney disease. Widespread arterial mineral in these patients disrupts vascular function and increases afterload on the heart. No therapeutic strategies currently exist to prevent or treat vascular calcification. Development of therapeutics is hindered by an incomplete understanding of the mineral formation process. Calcific mineral formation in the vascular wall begins in extracellular vesicles (EVs) that promote interactions between calcium and phosphate ions. Published data show that calcifying EV formation requires the presence of caveolin-1, a structural component of plasma membrane invaginations known as caveolae. However, the mechanisms through which caveolae may initiate calcifying EV formation remain unclear. The proposed study seeks to track the formation of calcifying EVs back to caveolae within vascular smooth muscle cells. We hypothesize that caveolae trafficking into the cell initiates calcifying EV formation and confers mineralization potential to the nascent vesicles. We will study the role of epidermal growth factor receptor (EGFR) as a caveolin-1 interactor and potential novel mediator of calcifying EV formation. Aim 1 of the study explores the caveolae-dependent mechanisms through which EVs form and promote mineralization. We will analyze the evolution of calcifying EVs as mineralization progresses both in vivo and in vitro. Aim 2 will test the therapeutic potential of a clinically-relevant strategy to alter caveolae trafficking and calcifying EV formation to treat vascular calcification.