Molecular and cellular biology of the urokinase/urokinase receptor -related vascular remodeling: role in vascular inflammation

尿激酶/尿激酶受体相关血管重塑的分子和细胞生物学：在血管炎症中的作用

• 批准号: 257233201
• 负责人: Professorin Dr. Inna Dumler
• 金额: --
• 依托单位: Klinik für Nieren- und Hochdruckerkrankungen
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/257233201?language=en
• 关键词: Molecular; cellular; biology; urokinase; receptor

This proposal addresses a role of the multifunctional urokinase receptor (uPAR) in vascular remodeling and inflammation. Our recent findings revealed one novel unexpected function for uPAR in these processes. We found that modified lipids initiate atherogenic signals triggering transition of vascular smooth muscle cells (VSMC) to pathophysiological phenotype and to expression of pro-inflammatory molecules. We provide evidence that uPAR was indispensable to mediate these effects. These findings point to yet unknown abilities of uPAR and modified lipids to affect vascular inflammation and remodeling by uncommon mechanisms. We observed uPAR structural and functional association with the pattern recognition receptors CD36 and TLR4 in response to oxLDL in VSMC. Though several interacting proteins have been identified for uPAR, its association neither with CD36 nor with TLR4 has been documented. These findings suggest complex of uPAR, CD36 and TLR4 as a functional cluster of pattern recognition receptors that recognizes and signals self-origin and most likely pathogen ligands and triggers inflammation. We hypothesize that, like lipopolysaccharide, the interaction of modified lipids with TLR4 may be enhanced by binding to a GPI-anchored protein. In VSMC, formation and activation of this functional unit in response to modified lipids may be a mechanism to trigger and propagate the atherogenic inflammation. Our data suggest that uPAR may govern specific inflammatory responses depending on its association with TLR4 or CD36 and function as a sensor for endogenous and exogenous pattern ligands. Identification of this molecular machinery and evaluation of its functional consequences in vivo represent the major goal of the present proposal. The expected results may provide additional new insights into the link among lipids, inflammation and atherosclerosis and further provide potential therapeutic or preventive targets for cardiovascular diseases.

这一建议解决了多功能尿激酶受体（uPAR）在血管重构和炎症中的作用。我们最近的发现揭示了uPAR在这些过程中的一个意想不到的新功能。我们发现修饰的脂质启动动脉粥样硬化信号，触发血管平滑肌细胞（VSMC）向病理生理表型和促炎分子表达的转变。我们提供的证据表明，uPAR是必不可少的调解这些影响。这些发现指出了uPAR和修饰脂质通过不寻常的机制影响血管炎症和重塑的未知能力。我们观察到uPAR与模式识别受体CD36和TLR4在VSMC中响应oxLDL的结构和功能关联。虽然已经发现了几种与uPAR相互作用的蛋白，但它既不与CD36也不与TLR4相关。这些发现表明，uPAR， CD36和TLR4复合物是一种功能模式识别受体簇，可识别并发出自源和最可能的病原体配体的信号，并引发炎症。我们假设，与脂多糖一样，修饰脂质与TLR4的相互作用可能通过与gpi锚定蛋白结合而增强。在VSMC中，这种功能单元的形成和激活是对修饰脂质的反应，可能是触发和传播致动脉粥样硬化炎症的机制。我们的数据表明，uPAR可能通过其与TLR4或CD36的关联来控制特定的炎症反应，并作为内源性和外源性模式配体的传感器。鉴定这种分子机制和评估其在体内的功能后果是本提案的主要目标。预期的结果可能为脂质、炎症和动脉粥样硬化之间的联系提供新的见解，并进一步为心血管疾病提供潜在的治疗或预防靶点。