Endothelial Sphingolipid Synthesis and Tissue Inflammatory Response

内皮鞘脂合成和组织炎症反应

基本信息

批准号：
10534147
负责人：
Annarita Di Lorenzo
金额：
$ 45.68万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-11 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10534147
关键词：
Address Anabolism Apolipoprotein E Arterial Fatty Streak Atherosclerosis Binding Blood Pressure Blood Vessels Cause of Death Cell Nucleus Coronary Coronary Arteriosclerosis Coronary artery Data Development Disease Economic Burden Endoplasmic Reticulum Endothelium Enzymes G-Protein-Coupled Receptors Gene Activation Genetic Transcription Goals Grant Heart failure Homeostasis Human Hypertension Inflammation Inflammatory Inflammatory Response Injury Knock-out Knockout Mice Medical Membrane Proteins Metabolism Modeling Mortality Determinants Mus Myocardial Myocardial Infarction Names Operative Surgical Procedures Pathogenesis Pathologic Pathway interactions Phosphorylation Predisposition Process Production Public Health Reporter Reporting Research Resistance Role Rupture Signal Transduction Site Sphingolipids Sphingosine-1-Phosphate Receptor Stimulus Stress TNF gene Therapeutic Tissues Vascular Diseases atheroprotective coronary lesion coronary plaque drug discovery hemodynamics human disease in vivo innovation lipid mediator mouse model novel oxidized low density lipoprotein pharmacologic pressure serine palmitoyltransferase sphingosine 1-phosphate therapeutic target transcriptome vascular inflammation

项目摘要

Endothelial injury promotes the development of atherosclerosis at the site of disturbed flow. Sphingosine-1-phosphate (S1P), produced by sphingolipid metabolism, is a secreted lipid mediator that interacts with G protein-coupled receptors, named S1P1-5. Locally produced and circulating S1P activate S1P receptors, particularly S1P1 the most abundant in the endothelium, to maintain vascular homeostasis. Altered sphingolipid metabolism and S1P signaling has been implicated in vascular disease, including coronary artery diseases (CAD). The current grant led to several advances. First, we discovered a novel mechanism by which endothelial sphingolipid biosynthesis is regulated. Nogo-B, a membrane protein of the ER, highly expressed in blood vessels, binds to and inhibits serine palmitoyltransferase (SPT), the rate-limiting enzyme of the de novo sphingolipid production. Second, we revealed that Nogo-B/SPT interaction downregulates local S1P signaling contributing to inflammation, hypertension and heart failure. Third, we found that inflammatory stimuli and ox-LDL induce Nogo-B phosphorylation, which further inhibits SPT activity contributing to endothelial injury. Fourth, following TNF-α, the N-terminus of Nogo-B is cleaved and translocates to the nucleus to impact endothelial transcriptome. Our long-term goal is to understand how Nogo-B regulates local sphingolipid signaling and its impact on coronary functions in the pathogenesis of CAD. Our hypothesis is that Nogo-B controls endothelial-derived S1P signaling, which is a key regulator of vascular homeostasis and disease- thereby influencing coronary plaque progression. Mechanistically, we hypothesize that Nogo-B promotes vascular inflammation and diseases via two major mechanisms; SPT inhibition, thus disrupting locally-derived S1P signaling, and the activation of gene profile. The rational is that the discovery of new mechanisms regulating endothelial inflammation will provide potential therapeutic targets for CAD. For the renewal, we propose to: 1) Investigate the role of endothelial Nogo-B in the susceptibility of mice to coronary atherosclerosis; 2) Determine the importance of endothelial S1P signaling and its role as downstream effector of Nogo-B in the onset of coronary atherosclerosis; 3) Dissecting the mechanism of Nogo-B signaling in myocardial endothelial injury. This contribution is significant since will identify novel targets for the treatment of CAD, especially since available therapies have been only partially successful, and beyond the statins, there are currently no effective pharmacological strategies that effectively address vascular inflammation. The proposed research is innovative because we investigate the effects of altered sphingolipid homeostasis and S1P signaling on the progression of coronary atherosclerosis, by using a novel mouse model of CAD and myocardial infarction that better recapitulates the human disease, a heretofore-unexamined process.

内皮损伤促进了流动障碍部位的动脉粥样硬化的发展。由鞘脂代谢产生的鞘氨醇1-磷酸（S1P）是一种分泌的脂质介质，与G蛋白偶联受体相互作用，称为S1P1-5。本地生产和循环S1P 激活S1P受体，特别是S1P1内皮中最丰富的受体，以保持血管稳态。鞘脂代谢改变和S1P信号已在血管中隐含疾病，包括冠状动脉疾病（CAD）。目前的赠款导致了几项进步。首先，我们发现了一种新型机制，通过该机制调节内皮鞘脂生物合成。 Nogo-B，a 在血管中高度表达的ER的膜蛋白与串行结合并抑制棕榈酰转移酶（SPT），从头鞘脂生产的速率限制酶。第二，我们揭示了Nogo-B/SPT相互作用下调局部S1P信号传导，有助于炎症，高血压和心力衰竭。第三，我们发现炎症刺激和OX-LDL 诱导Nogo-B磷酸化，这进一步抑制了导致内皮损伤的SPT活性。第四，在TNF-α之后，将Nogo-B的N末端裂解并易位到核以撞击内皮转录组。我们的长期目标是了解Nogo-B如何调节本地鞘脂信号及其对CAD发病机理中冠状动脉功能的影响。我们的假设是 Nogo-B控制内皮衍生的S1P信号，它是血管稳态的关键调节剂和疾病，从而影响冠状斑块的进展。从机械上讲，我们假设 Nogo-B通过两种主要机制促进血管感染和疾病。 SPT抑制作用破坏局部衍生的S1P信号传导和基因谱的激活。理性是发现调节内皮炎症的新机制将提供潜在的治疗 CAD的目标。对于续约，我们建议：1）研究内皮Nogo-B在小鼠对冠状动脉粥样硬化的敏感性； 2）确定内皮S1P的重要性信号传导及其在冠状动脉粥样硬化发作中作为Nogo-B的下游效应子的作用； 3）解剖心肌内皮损伤中Nogo-B信号传导的机制。这种贡献很重要，因为将确定CAD治疗的新目标，尤其是因为可用的疗法仅是部分成功的，除了他汀类药物之外，目前没有有效解决血管炎症的有效药理策略。提议研究具有创新性，因为我们研究了鞘脂稳态改变和S1P的影响通过使用新型CAD的小鼠模型和心肌梗死可以更好地概括人类疾病，这是一种迄今为止未经证明的过程。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sphingosine-1-phosphate controls endothelial sphingolipid homeostasis via ORMDL.

1-磷酸鞘氨醇通过 ORMDL 控制内皮鞘脂稳态。

DOI：
10.15252/embr.202254689
发表时间：
2023
期刊：
EMBO reports
影响因子：
7.7
作者：
Sasset,Linda;Chowdhury,KamrulH;Manzo,OnorinaL;Rubinelli,Luisa;Konrad,Csaba;Maschek,JAlan;Manfredi,Giovanni;Holland,WilliamL;DiLorenzo,Annarita
通讯作者：
DiLorenzo,Annarita

Early Morphofunctional Changes in AngII-Infused Mice Contribute to Regional Onset of Aortic Aneurysm and Dissection.

DOI：
10.1159/000509545
发表时间：
2020
期刊：
Journal of vascular research
影响因子：
1.7
作者：
Aslanidou L;Trachet B;Sasset L;Lovric G;Stergiopulos N;Di Lorenzo A
通讯作者：
Di Lorenzo A

Sphingolipid De Novo Biosynthesis: A Rheostat of Cardiovascular Homeostasis.

DOI：
10.1016/j.tem.2016.07.005
发表时间：
2016-11
期刊：
Trends in endocrinology and metabolism: TEM
影响因子：
0
作者：
Sasset L;Zhang Y;Dunn TM;Di Lorenzo A
通讯作者：
Di Lorenzo A

Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure.

DOI：
10.1038/nm.3934
发表时间：
2015-09
期刊：
Nature medicine
影响因子：
82.9
作者：
Cantalupo A;Zhang Y;Kothiya M;Galvani S;Obinata H;Bucci M;Giordano FJ;Jiang XC;Hla T;Di Lorenzo A
通讯作者：
Di Lorenzo A

S1PR1 (Sphingosine-1-Phosphate Receptor 1) Signaling Regulates Blood Flow and Pressure.