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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.

内皮损伤促进血流紊乱部位动脉粥样硬化的发展。

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

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.