SPHINGOLIPID BIOLOGY OF MACROPHAGE IN CORONARY ATHEROSCLEROSIS DEVELOPMENT AND PROGRESSION

冠状动脉粥样硬化发生和进展中巨噬细胞的鞘脂生物学

• 批准号: 10542823
• 负责人: Annarita Di Lorenzo
• 金额: $ 60.47万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542823
• 关键词: Address; Anabolism; Apolipoprotein E; Apoptosis; Arterial Fatty Streak; Atherosclerosis; Binding; Biological Process; Biology; Cardiovascular Physiology; Cardiovascular system; Carotid Arteries; Cause of Death; Cell Survival; Cell physiology; Cells; Ceramides; Cholesterol; Cholesterol Esters; Clinical; Complex; Coronary; Coronary Arteriosclerosis; Data; Development; Disease; Disease Progression; Down-Regulation; Economic Burden; Endoplasmic Reticulum; Endothelium; Enzymes; Event; Foam Cells; G-Protein-Coupled Receptors; Genetic; Genetic Transcription; Goals; Grant; Health; Heart failure; Heterogeneity; Human; Hypertension; Immune; Inflammation; Inflammatory; Lesion; Lipids; Macrophage; Mammals; Mediator; Membrane; Membrane Proteins; Metabolic Pathway; Metabolism; Modeling; Molecular; Mortality Determinants; Mus; Myocardial Infarction; Names; Operative Surgical Procedures; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphorylation; Plasma; Play; Population; Predisposition; Process; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Public Health; Regulation; Reporting; Research; Role; Rupture; Signal Transduction; Signaling Molecule; Sphingolipids; TNF gene; Testing; Therapeutic; Up-Regulation; acetyl-LDL; aortic valve; cell growth; cholesterol biosynthesis; coronary lesion; drug discovery; genetic approach; human disease; immune function; innovation; insight; metabolomics; mouse model; novel; oxidized low density lipoprotein; pharmacologic; serine palmitoyltransferase; sphingosine 1-phosphate; therapeutic development; therapeutic target; vascular inflammation

Inflammatory macrophages play a key role in the development and progression of the atherosclerosis, leading to myocardial infarction (MI). Sphingolipids are both membrane components and signaling molecules. Ceramide and Sphingosine-1-phosphate (S1P), bioactive and interchangeable sphingolipids, regulate a variety of cellular processes, including cell growth and survival, apoptosis, and immune and cardiovascular functions. As cholesterol, altered sphingolipid metabolism has been implicated in atherosclerosis. Whereas extensive studies on molecular regulation of cholesterol biosynthesis led to the discovery of statins, widely used lowering-cholesterol drugs, how sphingolipid biosynthesis is regulated and its pathophysiological implication are poorly understood. In this regard, our lab discovered a novel mechanism by which sphingolipid biosynthesis is regulated in mammals. Nogo-B, a membrane protein of the ER, binds to and inhibits serine palmitoyltransferase (SPT), the rate-limiting enzyme of the sphingolipid de novo biosynthesis[11]. Mice lacking Nogo-B are protected from inflammation, hypertension and heart failure, in part via endothelial S1P signaling. Our long-term goal is to understand how sphingolipid metabolism and signaling is regulated and its impact on coronary atherosclerosis development and progression. Recently, we developed a novel mouse model able to develop of coronary lesions, that progress to disruption (rupture, erosion) or occlusion leading to MI. Our hypothesis that Nogo-B downregulates SL metabolism and signaling, mainly ceramide and S1P, to control macrophage functions in coronary inflammation, atherosclerosis development and progression to MI. The rational is that the discovery of new mechanisms regulating the development and progression of atherosclerosis will provide potential therapeutic targets for coronary artery disease. Thus, we propose to: 1) investigate the role of MΦ Nogo-B in the susceptibility of mice to coronary atherosclerosis development and progression to MI; 2) Decipher the impact of Nogo-B-regulated ceramide and S1P signaling on MΦ biology and mechanistic insights. This contribution is significant since will identify novel targets for the treatment of coronary artery disease, 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 a relevant but understudied metabolic pathway by using a novel mouse model of coronary atherosclerosis with progression to MI that better recapitulates the human disease, a heretofore-unexamined process.

炎症性巨噬细胞在动脉粥样硬化的发展和发展中起关键作用， 导致心肌梗塞（MI）。鞘脂是膜成分和信号传导 分子。神经酰胺和鞘氨醇1-磷酸（S1P），生物活性和可互换 鞘脂，调节各种细胞过程，包括细胞生长和生存，凋亡和 免疫和心血管功能。作为胆固醇，改变的鞘脂代谢已经改变了 在动脉粥样硬化中实施。而对胆固醇分子调节的广泛研究 生物合成导致他汀类药物的发现，广泛使用的降低胆固醇药物，如何鞘脂 生物合成受到调节，其病理生理意义的理解很少。 在这方面，我们的实验室发现了一种新的机制 哺乳动物。 Nogo-B是ER的膜蛋白，与丝氨酸棕榈托酚转移酶结合并抑制 （SPT），鞘脂de从头生物合成的速率限制酶[11]。缺乏Nogo-B的老鼠是 免受炎症，高血压和心力衰竭的保护，部分通过内皮S1P信号传导。 我们的长期目标是了解如何调节鞘脂代谢和信号传导 对冠状动脉粥样硬化发展和进展的影响。 最近，我们开发了一种新型的鼠标模型来开发冠状动脉病变，从而发展为 破坏（破裂，侵蚀）或遮挡导致MI。我们的假设Nogo-B下调了SL 代谢和信号传导，主要是神经酰胺和S1P，以控制冠状动脉的巨噬细胞功能 炎症，动脉粥样硬化发育和向MI的发展。理性的是发现 调节动脉粥样硬化发展和进展的新机制将提供潜力 冠状动脉疾病的治疗靶标。也就是说：1）研究Mφ的作用 小鼠对冠状动脉粥样硬化发育和进展为MI的敏感性的Nogo-B； 2） 破译Nogo-B调节的神经酰胺和S1P信号对Mφ生物学和机械的影响 见解。这种贡献很重要，因为将确定治疗冠状动脉的新目标 动脉疾病，尤其是因为可用的疗法只是部分成功，并且超出了 他汀类药物目前没有有效解决血管的有效药物策略 炎。拟议的研究具有创新性，因为我们研究了相关但知识的 使用新型的冠状动脉粥样硬化小鼠模型与Mi的进展，代谢途径 这样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。