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发展中起关键作用。 导致心肌梗死(MI)。鞘磷脂既是膜成分，也是信号转导 分子。神经酰胺和鞘氨醇-1-磷酸(S1P)，生物活性和可互换 鞘磷脂，调节各种细胞过程，包括细胞生长和存活，细胞凋亡，和 免疫和心血管功能。作为胆固醇，鞘脂代谢的改变一直是 与动脉粥样硬化有关。鉴于对胆固醇分子调控的广泛研究 生物合成导致了他汀类药物的发现，他汀类药物被广泛应用于降胆固醇药物，鞘脂是如何 生物合成受到调控，其病理生理意义尚不清楚。 在这方面，我们的实验室发现了一种新的机制，通过这种机制来调节鞘磷脂的生物合成。 哺乳动物。内质网膜蛋白Nogo-B结合并抑制丝氨酸棕榈酰转移酶 (SPT)，鞘磷脂新生物合成的限速酶[11]。缺乏Nogo-B的小鼠 防止炎症、高血压和心力衰竭，部分是通过内皮S1P信号。 我们的长期目标是了解鞘脂新陈代谢和信号是如何调节的，以及它的 对冠状动脉粥样硬化的发展和进展的影响。 最近，我们开发了一种新的能够形成冠状动脉病变的小鼠模型，该模型的进展是 导致心肌梗死的破裂(破裂、侵蚀)或闭塞。我们关于Nogo-B下调SL的假设 控制冠状动脉巨噬细胞功能的代谢和信号转导，主要是神经酰胺和S1P 炎症、动脉粥样硬化的发展和进展为心肌梗死。合乎情理的是， 调控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M-Φ的作用 Nogo-B在小鼠冠状动脉粥样硬化发生和进展为心肌梗死的易感性中的作用 解读NOGO-B调节的神经酰胺和S1P信号对M-Φ生物学和机制的影响 洞察力。这一贡献意义重大，因为它将确定治疗冠心病的新靶点。 动脉疾病，特别是因为现有的治疗方法只取得了部分成功，而且超出了 他汀类药物，目前还没有有效的药物策略来有效地解决血管 发炎。拟议的研究是创新的，因为我们调查了一个相关但未被研究的 利用一种新的冠状动脉粥样硬化进展为心肌梗死小鼠模型的代谢途径 这更好地概括了人类疾病，这是一个迄今未被研究的过程。