Mechanisms of sphingolipid signaling in vascular health and disease

项目总结 生物活性脂质介质信号系统与复杂的血管、免疫和神经系统同时进化 脊椎动物系统。我的实验室发现了1-磷酸鞘氨醇(S1P)受体，并已 有助于我们了解这种脂质介体如何调节血管和免疫系统。S1P 受体现在是一种被批准用于治疗复发的药物(Fingolimod/Gilenya)的靶点， 缓解多发性硬化症。大量的努力被用于开发第二代S1P受体- 几种免疫、肿瘤和血管疾病的靶向治疗。然而，我们对此的理解 S1P信号在多种疾病中的作用有限，基于S1P受体的治疗药物受到影响 从重大的机制为基础的不良事件。这项建议旨在填补我们对以下方面知识的空白 S1P信号如何调节血管疾病并开发新的治疗策略来减少血管 疾病进展和血管内皮细胞功能的恢复是心血管健康的重要因素。具体来说， 我们将重点介绍S1P分子伴侣、与S1P结合的蛋白质分子和靶受体信号转导 激活特定生物反应的复合体。特别是，我们将探索通过哪些机制 高密度脂蛋白结合的S1P通过激活S1PR1抑制血管内皮损伤和促进血管稳态 信号复合体。第二，我们将探索S1PR1信号系统如何调节剪切力- 诱导血管内皮细胞动态平衡。受体信号复合体的机制细节 转换动态层流剪切力和病理扰动产生的生物力学力 剪裁成细胞内生化信号和转录输出将在内皮细胞中阐明 体外和体内。第三，自身免疫相关细胞因子(I型干扰素)通过何种机制 加重血管内皮损伤和加速血管疾病将在小鼠模型中探索并相互关联 从正常人和系统性红斑狼疮(SLE)患者分离内皮细胞。最后，我们 将开发稳定的重组载脂蛋白融合蛋白，将S1P运送到内皮S1PR促进 血管动态平衡，减少血管内皮损伤。这种生物疗法在动物模型中的应用 高血压、心肌缺血/再灌注损伤、异常血管生成和组织纤维化 检查过了。这些研究有望全面理解S1P信号如何 促进血管内稳态并导致开发控制血管损伤的新方法 以及使用心血管靶向S1P疗法的疾病。

PROJECT SUMMARY Bioactive lipid mediator signaling systems evolved coincidently with complex vascular, immune and nervous systems of vertebrates. My laboratory discovered the sphingosine 1-phosphate (S1P) receptor and have contributed to our knowledge of how this lipid mediator regulates the vascular and immune systems. S1P receptor is now a target for a drug (Fingolimod/ Gilenya) that is approved for the treatment of relapsing, remitting multiple sclerosis. Much effort is directed towards developing second generation S1P receptor- targeted therapeutics for several immune, oncologic and vascular diseases. However, our understanding of how S1P signaling contributes to various diseases is limited and S1P receptor-based therapeutic agents suffer from significant mechanism-based adverse events. This proposal aims to fill the gap in our knowledge about how S1P signaling regulates vascular disease and develop novel therapeutic strategies to reduce vascular disease progression and restore endothelial function, an important factor in cardiovascular health. Specifically, we will focus on the S1P chaperones, protein molecules that bind to S1P and target receptor signaling complexes to activate specific biological responses. In particular, we will explore the mechanisms by which HDL-bound S1P suppresses endothelial injury and promote vascular homeostasis by the activation of S1PR1 signaling complexes. Second, we will explore how the S1PR1 signaling system regulates shear stress- induced vascular endothelial cell homeostasis. Mechanistic details of receptor signaling complexes that translate biomechanical forces that result from homeostatic laminar shear stress and pathologic disturbed shear into intracellular biochemical signals and transcriptional output will be elucidated in endothelial cells in vitro and in vivo. Third, mechanisms by which autoimmunity-associated cytokines (type-I interferons) to exacerbate endothelial injury and accelerate vascular disease will be explored in mouse models and correlated with endothelial cells isolated from normal and patients with systemic lupus erythematosus (SLE). Finally, we will develop stabilized recombinant ApoM fusion protein to deliver S1P to endothelial S1PRs to promote vascular homeostasis and reduce endothelial injury. The use of this biological therapeutic in animal models of hypertension, myocardial ischemia/ reperfusion injury, abnormal angiogenesis and tissue fibrosis will be examined. These studies are anticipated to lead to comprehensive understanding of how S1P signaling promotes vascular homeostasis and lead to the development of novel approaches to control vascular injury and disease using cardiovascular targeted S1P therapeutics.