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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

基本信息

批准号：
10536682
负责人：
Timothy Tun Hla
金额：
$ 88.77万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
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/10536682
关键词：
Acceleration Adverse event Animal Model Autoimmune Diseases Autoimmunity Binding Biochemical Biological Biological Response Modifier Therapy Biomechanics Blood Vessels Blood flow Cardiovascular Diseases Cardiovascular system Cell Separation 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 Molecular Chaperones Myocardial Reperfusion Injury Nervous System Output Pathologic Patients Pharmaceutical Preparations Proteins Receptor Signaling Recombinants Relapsing-Remitting Multiple Sclerosis 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 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

项目摘要

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.

项目摘要生物活性脂质介体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。我的实验室发现了鞘氨醇1-磷酸（S1 P）受体，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）的靶点，该药物被批准用于治疗复发性，缓解多发性硬化症许多努力是针对开发第二代S1 P受体- 用于多种免疫、肿瘤和血管疾病的靶向治疗。然而，我们对 S1 P信号传导对各种疾病的作用是有限的，严重的机制性不良事件。这项建议旨在填补我们对以下问题的认识上的差距 S1 P信号传导如何调节血管疾病，并开发新的治疗策略以减少血管疾病疾病进展和恢复内皮功能，心血管健康的重要因素。具体地说，我们将集中在S1 P分子伴侣，结合到S1 P和靶受体信号传导的蛋白质分子复合物以激活特定的生物反应。特别是，我们将探讨 HDL结合的S1 P通过激活S1 PR 1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S1 PR 1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，转换由稳态层流剪切应力和病理干扰引起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阐明，体外和体内。第三，自身免疫相关细胞因子（I型干扰素）将在小鼠模型中探索加剧内皮损伤和加速血管疾病的相关性，用分离自正常人和系统性红斑狼疮（SLE）患者的内皮细胞。最后我们将开发稳定的重组ApoM融合蛋白，将S1 P递送至内皮S1 PR，血管内环境稳定和减少内皮损伤。这种生物治疗剂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将是考察预计这些研究将有助于全面了解S1 P信号传导促进血管内稳态，并导致控制血管损伤的新方法的发展以及使用心血管靶向S1 P治疗的疾病。

项目成果

期刊论文数量（29）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bioluminescence imaging of G protein-coupled receptor activation in living mice.

DOI：
10.1038/s41467-017-01340-7
发表时间：
2017-10-27
期刊：
Nature communications
影响因子：
16.6
作者：
Kono M;Conlon EG;Lux SY;Yanagida K;Hla T;Proia RL
通讯作者：
Proia RL

Sphingosine 1-phosphate: Lipid signaling in pathology and therapy.

DOI：
10.1126/science.aar5551
发表时间：
2019-10-18
期刊：
Science (New York, N.Y.)
影响因子：
0
作者：
Cartier A;Hla T
通讯作者：
Hla T

Aging Suppresses Sphingosine-1-Phosphate Chaperone ApoM in Circulation Resulting in Maladaptive Organ Repair.

DOI：
10.1016/j.devcel.2020.05.024
发表时间：
2020-06-22
期刊：
Developmental cell
影响因子：
11.8
作者：
Ding BS;Yang D;Swendeman SL;Christoffersen C;Nielsen LB;Friedman SL;Powell CA;Hla T;Cao Z
通讯作者：
Cao Z

Sphingosine 1-Phosphate Receptor 1 Signaling Maintains Endothelial Cell Barrier Function and Protects Against Immune Complex-Induced Vascular Injury.