Sphingolipid signaling in age-associated vascular pathology

与年龄相关的血管功能下降是器官功能、活力、 对应激的抵抗力和心血管疾病和炎症性疾病的发病率/死亡率增加 疾病。我们的实验室在两个脂质介体领域做出了长期的贡献 -即调节血管系统的鞘氨醇1-磷酸(S1P)和前列环素(PGI2) 和炎症过程。我们最近的数据表明，S1P和PGI2的年龄相关性下降 信号轴导致血管功能障碍和疾病，从而导致与年龄相关的疾病 器官功能衰退。具体地说，S1P信号从动态平衡转变为促进- 衰老过程中的炎症和损伤状态。临床研究表明，减毒的S1P和 PGI2信号轴与心血管疾病发病率的增加有关。这项建议是 基于这样的前提，即脂质中介信号通路的失调在 与年龄相关的炎症和心血管疾病，导致显著的功能下降， 死亡率和发病率。该提案的中心假设是血管保护作用减弱 血管内皮细胞中的S1P通路与年龄相关的血管功能障碍和疾病有关。 这种与年龄相关的过程影响到主动脉、视网膜和 以一种特殊的、机械上易于处理的方式来削弱器官功能。我们的目标是定义 小鼠肝、视网膜和主动脉异种内皮细胞的转录组 衰老。类似的分析也将在S1PR1信号通路参与的老年小鼠中进行。 血管内皮细胞的衰弱是由遗传因素造成的。第二，我们将定义用于 内皮细胞中的PGI2信号与S1PR1协同增强血管保护作用 发出信号并促进血管健康。第三，我们将阐明年龄- 依赖诱导S1PR2拮抗S1PR1并导致血管功能障碍 发炎。小鼠遗传模型以及S1PR2的药理抑制剂将是 测试以确定它们在治疗与年龄相关的血管功能障碍和疾病方面的有效性。 这些研究有望带来新的见解，通过哪些脂质介体信号通路 导致年龄依赖性血管功能障碍和疾病，这最终可能导致新的 对抗与年龄相关的器官功能障碍和衰退的治疗策略。

Age-related decline in vascular function is a key factor in decreased organ function, vitality, resistance to stress and increased morbidity/ mortality from cardiovascular and inflammatory diseases. Our laboratory has made long-standing contributions in the areas of two lipid mediators – namely, sphingosine 1-phosphate (S1P) and prostacyclin (PGI2), which regulate vascular system and inflammatory processes. Our recent data suggest that age-dependent decline in S1P and PGI2 signaling axes contribute to vascular dysfunction and disease, thereby contributing to age-related functional decline in organs. Specifically, S1P signaling shifts from homeostatic to pro- inflammatory and injurious states during aging. Clinical studies show that attenuated S1P and PGI2 signaling axes contribute to increased incidence of cardiovascular disease. This proposal is based on the premise that that dysregulation of lipid mediator signaling pathways are important in age-related inflammatory and cardiovascular diseases that lead to significant functional decline, mortality and morbidity. The central hypothesis of the proposal is that decreased vasculoprotective S1P pathway in the endothelium contributes to age-associated vascular dysfunction and disease. Such age-associated processes affect the heterogenous vascular endothelium of aorta, retina and liver in a specific, mechanistically-tractable way to attenuate organ function. We aim to define the transcriptome of heterogenous endothelial cells from liver, retina and aorta of the mouse during aging. Similar analysis will also be done from aged mice in which S1PR1 signaling pathway in the endothelium is attenuated by genetic means. Second, we will define the mechanisms by which PGI2 signaling in the endothelium synergizes with the S1PR1 to enhance vasculoprotective signaling and promote vascular health. Third, we will elucidate the mechanisms by which age- dependent induction of S1PR2 antagonizes S1PR1 and induce vascular dysfunction and inflammation. Mouse genetic models as well as pharmacological inhibitors of S1PR2 will be tested to determine their utility in the treatment of age-related vascular dysfunction and disease. These studies are anticipated to lead to new insights by which lipid mediator signaling pathways contribute to age-dependent vascular dysfunction and disease, which could ultimately lead to novel therapeutic strategies to combat age-related organ dysfunction and decline.