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: 10321959
• 负责人: Annarita Di Lorenzo
• 金额: $ 60.13万
• 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/10321959
• 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; Low-Density Lipoproteins; Mammals; Mediator of activation protein; Membrane; Membrane Proteins; Metabolic Pathway; Metabolism; Modeling; Molecular; Mortality Determinants; Mus; Myocardial Infarction; Names; Operative Surgical Procedures; Pathway interactions; Pharmaceutical Preparations; Pharmacology; 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; aortic valve; base; cell growth; cholesterol biosynthesis; coronary lesion; drug discovery; genetic approach; human disease; immune function; innovation; insight; macrophage; metabolomics; mouse model; novel; oxidized low density lipoprotein; 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.

炎性巨噬细胞在动脉粥样硬化的发生和发展中起关键作用， 导致心肌梗塞（MI）。鞘脂既是膜成分，也是信号传导 分子。神经酰胺和鞘氨醇-1-磷酸（S1 P），具有生物活性且可互换 鞘脂调节多种细胞过程，包括细胞生长和存活、细胞凋亡， 免疫和心血管功能。与胆固醇一样， 与动脉粥样硬化有关然而，对胆固醇分子调控的广泛研究 生物合成导致他汀类药物的发现，广泛使用的降低胆固醇的药物，如何鞘脂 生物合成受到调节，其病理生理学意义知之甚少。 在这方面，我们的实验室发现了一种调节鞘脂生物合成的新机制， 哺乳动物Nogo-B是内质网的一种膜蛋白，可结合并抑制丝氨酸棕榈酰转移酶 (SPT)，鞘脂从头生物合成的限速酶[11]。缺乏Nogo-B的小鼠 部分通过内皮S1 P信号传导，防止炎症、高血压和心力衰竭。 我们的长期目标是了解鞘脂代谢和信号传导是如何调节的， 对冠状动脉粥样硬化发展和进展的影响。 最近，我们开发了一种新的小鼠模型，能够发展冠状动脉病变， 破裂（破裂、侵蚀）或闭塞导致MI。我们假设Nogo-B下调SL 代谢和信号传导，主要是神经酰胺和S1 P，以控制冠状动脉中的巨噬细胞功能。 炎症、动脉粥样硬化发展和进展为MI。合理的解释是， 调节动脉粥样硬化发展和进展的新机制将提供潜在的 冠状动脉疾病的治疗靶点。因此，我们建议：1）研究MΦ的作用 Nogo-B在小鼠冠状动脉粥样硬化发生和进展为MI的易感性中的作用; 2） 解读Nogo-B调节的神经酰胺和S1 P信号对MΦ生物学的影响及其机制 见解.这一贡献是重要的，因为将确定治疗冠状动脉粥样硬化的新靶点。 动脉疾病，特别是因为现有的治疗方法只取得了部分成功， 他汀类药物，目前没有有效的药理学策略，有效地解决血管 炎症拟议的研究是创新的，因为我们调查了一个相关的，但研究不足， 冠状动脉粥样硬化进展为心肌梗死的新型小鼠模型 更好地概括了人类的疾病，一个迄今为止未被研究过的过程。