Mechanisms of sphingolipid signaling in vascular health and disease

血管健康和疾病中鞘脂信号传导的机制

• 批准号: 10365913
• 负责人: Timothy Tun Hla
• 金额: $ 89.13万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-18 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10365913
• 关键词: Adverse event; Animal Model; Autoimmune Diseases; Autoimmunity; Binding; Biochemical; Biological; Biological Response Modifier Therapy; Biomechanics; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular system; Chimeric Proteins; Complex; Development; Disease; Disease Progression; Endothelial Cells; Endothelium; Event; Fibrosis; Generations; Genetic Transcription; Health; High Density Lipoproteins; Homeostasis; Hypertension; Immune; Immune system; In Vitro; Injury; Interferon Type I; Knowledge; Laboratories; Lead; Molecular Chaperones; Myocardial Ischemia; Nervous system structure; Output; Pathologic; Patients; Pharmaceutical Preparations; Proteins; Receptor Signaling; Recombinants; Relapsing-Remitting Multiple Sclerosis; Reperfusion Injury; Signal Transduction; Sphingolipids; Sphingosine-1-Phosphate Receptor; System; Systemic Lupus Erythematosus; Therapeutic; Therapeutic Agents; Tissues; Translating; Vascular Diseases; Vascular Endothelial Cell; Vascular System; Vertebrates; angiogenesis; base; cardiovascular health; cytokine; in vivo; lipid mediator; mouse model; novel strategies; novel therapeutic intervention; novel therapeutics; response; shear stress; sphingosine 1-phosphate; targeted treatment; vascular injury

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.

项目概要 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质如何调节血管和免疫系统。 S1P 受体现在是一种药物（芬戈莫德/ Gilenya）的靶标，该药物被批准用于治疗复发性、 缓解多发性硬化症。大量努力致力于开发第二代 S1P 受体 - 针对多种免疫、肿瘤和血管疾病的靶向治疗。然而，我们的理解 S1P 信号传导对各种疾病的影响有限，基于 S1P 受体的治疗药物受到影响 来自基于机制的重大不良事件。该提案旨在填补我们在以下方面的知识空白： 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 疾病进展和恢复内皮功能，这是心血管健康的重要因素。具体来说， 我们将重点关注 S1P 伴侣、与 S1P 结合的蛋白质分子和目标受体信号传导 复合物来激活特定的生物反应。特别是，我们将探讨其机制 HDL 结合的 S1P 通过激活 S1PR1 抑制内皮损伤并促进血管稳态 信号复合物。其次，我们将探讨S1PR1信号系统如何调节剪切应力—— 诱导血管内皮细胞稳态。受体信号复合物的机制细节 转化由稳态层流剪切应力和病理扰动产生的生物力学力 剪切成细胞内生化信号和转录输出将在内皮细胞中得到阐明 体外和体内。第三，自身免疫相关细胞因子（I型干扰素）的作用机制 将在小鼠模型中探索加剧内皮损伤并加速血管疾病的相关研究 使用从正常人和系统性红斑狼疮 (SLE) 患者中分离的内皮细胞。最后，我们 将开发稳定的重组 ApoM 融合蛋白，将 S1P 递送至内皮 S1PR，以促进 血管稳态并减少内皮损伤。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 检查了。这些研究预计将有助于全面了解 S1P 信号如何传递 促进血管稳态并导致控制血管损伤的新方法的开发 和疾病使用心血管靶向 S1P 疗法。