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

用于解决主动脉瘤和破裂的新型专业化脂质介质

• 批准号: 10645097
• 负责人: Ashish Kumar Sharma
• 金额: $ 48.91万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645097
• 关键词: 5' -AMP-activated protein kinase; Abdominal Aortic Aneurysm; Acute; Affect; Aftercare; Aneurysm; Animals; Aorta; Aortic Aneurysm; Aortic Rupture; Aortitis; Apoptotic; Attenuated; Base Excision Repairs; Blood Vessels; CD59 Antigen; CMKLR1 gene; Cause of Death; Cells; Chronic; Chronic Obstructive Pulmonary Disease; Chronic Phase; Clinical; Coculture Techniques; Coupled; DNA glycosylase; Data; Diameter; 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; IL17 gene; Immune; In Vitro; Infiltration; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-10; Lipids; Lipoxins; Liquid Chromatography; MMP2 gene; Macrophage; Matrix Metalloproteinases; Measures; Mediating; Mediator; Medical; Methodology; Mitochondrial DNA; Modeling; Mus; Necrosis; Omega-3 Fatty Acids; Omega-6 Fatty Acids; 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; clinical application; clinical risk; clinical translation; cytokine; experimental study; human tissue; immune cell infiltrate; immunoregulation; in vivo; lipid mediator; 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-derived 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 the 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-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.

项目摘要 腹主动脉瘤（AAA）形成和随后的主动脉破裂会导致猝死，是一个 重大的临床问题，目前没有已知的医疗治疗。我们最近的研究已经 表征了专门的促进介体（SPM）的受保护作用，该作用为ω-3衍生的脂质 衍生物，即通过调节M1/M2有效地减弱AAA形成的Resolvin（RV）D1 巨噬细胞极化。在此提案中，我们将描述生物活性的表型和机制 SPMS的同工型，即Resolvins（RVD1），Maresins（Mar-1），Protectins（PD-1）和Lipoxins（LXB4）（LXB4） 可以导致主动脉瘤形成的溶液并预防主动脉损伤。首先，我们将测量SPM 通过电喷雾串联量的鼠实验AAA模型的人AAA患者和主动脉组织 耦合到液相色谱（LC/ESI-MS/MS）的光谱法，这是一种敏感的分析方法 用于脂质介质的定性和定量分析。然后，我们将表征协同作用 这些SPM生物活性同工型在我们的鼠AAA和主动脉破裂模型中的反应。最后，我们会的 使用SPMS的生物活性同工型的特定机制，即使用RVD1，MAR-1，PD-1和LXB4使用 体内和体外研究。我们的初步数据表明，使用MAR-1治疗可以防止 与主动脉平滑肌细胞-TGF-β1信号相关的动脉瘤形成的最新进展。 报道表明，氧化的线粒体（MT）DNA充当形成的损伤图案分子 篮网，但在AAAS中仍有待描述。因此，MAR-1在促进巨噬细胞中的作用 与净有关 在人AAA组织以及实验鼠模型中也将阐明形成。而且，我们 将量化SPM相关的G蛋白偶联受体（GPCR），即（ALX/FPR2，GPR32，GPR18和 chemr23）在AAA中发出信号。具体而言，通过AMP激活蛋白激酶（AMPK）TO RVD1/FPR2信号传导 GM-CSF和HMGB1的调节促炎性巨噬细胞分泌将在AAA形成中决定。 因此，我们将表征SPM的独特能力处理预先形成的动脉瘤并防止 通过调节RVD1-FPR2信号传导，mtDNA依赖性Netosis，促进来通过主动脉破裂 常规细胞增多和调节SMC依赖性TGF-β1信号传导。这种多方面的针对性方法 特定的SPM同工型展示了一种临床适用的理论策略，用于治疗慢性主动脉 通过靶向巨噬细胞，中性粒细胞和平滑肌细胞进行炎症和血管重塑。我们的 科学的前提是对这些促分解脂质衍生介质的作用进行深入分析 在动脉瘤形成的慢性模型中。重要的是，我们将测试这些的严格性和可重复性 动物研究确定这些转变是否使用离体向前外植体在人体组织中发生。