Diversity Supplement: Novel specialized pro-resolving lipid mediators in resolution of aortic aneurysms and rupture

多样性补充：解决主动脉瘤和破裂的新型专业化脂质介质

• 批准号: 10239324
• 负责人: Ashish Kumar Sharma
• 金额: $ 2.72万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-19 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10239324
• 关键词: 5' -AMP-activated protein kinase; Abdominal Aortic Aneurysm; Acute; Affect; Aftercare; Aneurysm; Animals; Aortic Aneurysm; Aortic Rupture; Aortitis; Apoptotic; Attenuated; Base Excision Repairs; Blood Vessels; CD59 Antigen; CMKLR1 gene; Caliber; Cause of Death; Cells; Chronic; Chronic Obstructive Airway Disease; Clinical; Coculture Techniques; Coupled; Culture Techniques; DNA glycosylase; Data; Elastin; Extracellular Matrix Degradation; FPR2 gene; Failure; G-Protein-Coupled Receptors; GPR18 receptor; GPR32 gene; Gender; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; HMGB1 gene; Human; Hypertension; Immune; In Vitro; Infiltration; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-10; Interleukin-17; Lead; Lipids; Lipoxins; Liquid Chromatography; MMP2 gene; Matrix Metalloproteinases; Measures; Mediating; Mediator of activation protein; Medical; Methodology; Mitochondrial DNA; Modeling; Mus; Necrosis; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Oxides; Pathologic; Pathway interactions; Patients; Pattern; Phenotype; Plasma; Plasminogen Activator Inhibitor 1; Prevalence; Process; Protein Isoforms; Public Health; Race; Regulation; Reporting; Reproducibility; Resolution; Risk Factors; Role; Sampling; Serine Protease; Signal Transduction; Smoking; Smooth Muscle Myocytes; Sudden Death; TIMP1 gene; Testing; Therapeutic; Thrombus; Tissues; Transforming Growth Factor beta; Up-Regulation; Vascular remodeling; attenuation; attributable mortality; base; clinical application; clinical risk; clinical translation; cytokine; experimental study; human tissue; immunoregulation; in vivo; lipid mediator; macrophage; male; men; mitochondrial genome; mouse model; neutrophil; novel; oxidative damage; prevent; programmed cell death protein 1; receptor-mediated signaling; repair enzyme; response; synergism; tandem mass spectrometry; treatment strategy; uptake

PROJECT SUMMARY Abdominal aortic aneurysms (AAA) formation and subsequent aortic rupture can lead to sudden death and is a significant clinical problem with no currently known medical treatments available. Our recent studies have characterized a protective role of specialized pro-resolving mediators (SPMs) that are ω-3-fatty acid lipid derivatives i.e. Resolvin (Rv)D1 that effectively attenuates AAA formation via modulating the M1/M2 macrophage polarization. In this proposal, we will delineate the phenotype and mechanisms of bioactive isoforms of SPMs i.e. Resolvins (RvD1), Maresins (MaR-1), Protectins (PD-1) and Lipoxins (LxB4) that can lead to resolution of aortic aneurysm formation and prevent aortic rupture. First, we will measure SPMs in human AAA patients and aortic tissue from murine experimental AAA model via electrospray tandem mass spectrometry coupled to liquid chromatography (LC/ESI-MS/MS), which is a sensitive analytical methodology for the qualitative and quantitative analysis of lipid mediators. Then, we will characterize the synergistic response of these SPM bioactive isoforms in our murine AAA and aortic rupture models. Finally, we will delineate the specific mechanisms of the bioactive isoforms of SPMs i.e. RvD1, MaR-1, PD-1 and LxB4 using in vivo and in vitro studies. Our preliminary data demonstrates that treatment with MaR-1 can prevent the progression of aneurysm formation that is associated with aortic smooth muscle cell (SMC)-TGF-β1 signaling. Recent reports suggest that oxidized mitochondrial (mt) DNA acts as a damage associated pattern molecule to form NETs, but it remains to be characterized in AAAs. Therefore, the role of MaR-1 in promoting macrophage- dependent efferocytosis (the process of uptake of apoptotic/necrotic neutrophils) associated with NET formation will also be elucidated in human AAA tissue as well as experimental murine models. Moreover, we will quantify SPM-related G-protein coupled receptors (GPCR) i.e. (ALX/FPR2, GPR32, GPR18, and ChemR23) signaling in AAA. Specifically, RvD1/FPR2 signaling via AMP-activated protein kinase (AMPK) to regulate pro-inflammatory macrophage secretion of GM-CSF and HMGB1 will be deciphered in AAA formation. Therefore, we will characterize the unique ability of SPMs to treat preformed aneurysms and prevent aortic rupture by modulating RvD1-FPR2 signaling, mtDNA-dependent NETosis, promoting efferocytosis and modulating SMC-dependent TGF-β1 signaling. This multi-faceted targeted approach of specific SPM isoforms demonstrate a clinically applicable therapeutic strategy for treatment of chronic aortic inflammation and vascular remodeling by targeting macrophages, neutrophils and smooth muscle cells. Our scientific premise is to perform an in-depth analysis of the roles of these pro-resolving lipid derived mediators in the chronic models of aneurysm formation. Importantly, we will test the rigor and reproducibility of these animal studies to determine whether these transitions occur in human tissue using ex vivo aortic explants.

项目概要 腹主动脉瘤 (AAA) 形成和随后的主动脉破裂可导致猝死，是一种 我们最近的研究发现，目前尚无可用的已知医学治疗方法。 表征了特殊促分解介质 (SPM) 的保护作用，这些介质是 ω-3-脂肪酸脂质 衍生物，即 Resolvin (Rv)D1，可通过调节 M1/M2 有效减弱 AAA 的形成 在本提案中，我们将描述生物活性的表型和机制。 SPM 的亚型，即 Resolvins (RvD1)、Maresins (MaR-1)、Protectins (PD-1) 和 Lipoxins (LxB4)，可以 导致主动脉瘤形成消退并防止主动脉破裂首先，我们将测量 SPM。 通过电喷雾串联质量获得人类 AAA 患者和小鼠实验 AAA 模型的主动脉组织 光谱法与液相色谱法 (LC/ESI-MS/MS) 联用，这是一种灵敏的分析方法 然后，我们将表征脂质介质的协同作用。 最后，我们将研究这些 SPM 生物活性亚型在我们的鼠 AAA 和主动脉破裂模型中的反应。 使用以下方法描述 SPM 生物活性亚型（即 RvD1、MaR-1、PD-1 和 LxB4）的具体机制 我们的体内和体外研究表明，使用 MaR-1 治疗可以预防这种情况。 与主动脉平滑肌细胞 (SMC)-TGF-β1 信号传导相关的动脉瘤形成进展。 最近的报告表明，氧化线粒体 (mt) DNA 作为损伤相关模式分子， 形成 NET，但在 AAA 中仍有待表征，因此，MaR-1 在促进巨噬细胞中的作用。 与 NET 相关的依赖性胞吞作用（凋亡/坏死中性粒细胞的摄取过程） 还将在人类 AAA 组织以及实验鼠模型中阐明其形成。 将量化 SPM 相关的 G 蛋白偶联受体 (GPCR)，即（ALX/FPR2、GPR32、GPR18 和 ChemR23) AAA 中的信号传导，具体来说，RvD1/FPR2 信号传导通过 AMP 激活的蛋白激酶 (AMPK) 来实现 调节促炎巨噬细胞分泌 GM-CSF 和 HMGB1 将在 AAA 形成中被破译。 因此，我们将描述 SPM 治疗已形成动脉瘤和预防动脉瘤的独特能力。 通过调节 RvD1-FPR2 信号、mtDNA 依赖性 NETosis、促进主动脉破裂 胞吞作用和调节 SMC 依赖性 TGF-β1 信号传导。 特定的 SPM 亚型证明了治疗慢性主动脉粥样硬化的临床适用治疗策略 通过靶向巨噬细胞、中性粒细胞和平滑肌细胞来抑制炎症和血管重塑。 科学前提是对这些促溶解脂质衍生介质的作用进行深入分析 重要的是，我们将测试这些动物的严谨性和可重复性。 研究使用离体主动脉外植体来确定这些转变是否发生在人体组织中。