Targeting the Caveolae-Dependent Mechanism of Calcifying Extracellular Vesicle Formation

项目总结 血管钙化是心血管疾病发病率的最重要预测因子，尤其在 患有慢性肾脏疾病的个人。这些患者中广泛存在的动脉矿物质破坏了血管功能 并增加心脏的后负荷。目前还不存在预防或治疗血管疾病的治疗策略 钙化。对矿物质形成的不完全理解阻碍了治疗学的发展 进程。血管壁中钙质矿物的形成始于细胞外小泡(EVS)，它促进 钙和磷酸根离子之间的相互作用。已公布的数据显示，钙化EV的形成需要 存在小凹-1，这是质膜凹陷的一种结构成分，称为小窝。 然而，小窝可能启动钙化EV形成的机制尚不清楚。这个 拟议的研究试图追踪钙化EVS的形成，追溯到血管平滑肌内的小窝 细胞。我们假设空洞进入细胞后，会引发钙化EV的形成，并使 新生小泡的矿化潜力。我们将研究表皮生长因子受体(EGFR)的作用 作为小窝蛋白-1的相互作用因子和潜在的钙化EV形成的新介体。这项研究的目标1探索 EVS形成和促进矿化的洞穴依赖机制。我们将分析 在体内和体外，随着矿化的进展，钙化EVS的演变。Aim 2将测试治疗方法 改变空洞运输和钙化EV形成治疗血管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.