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

基本信息

批准号：
10032697
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
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10032697
关键词：
5&apos -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

项目摘要

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。表征了特殊的促解析介质 (SPM) 的保护作用，这些介质是 ω-3 衍生的脂质衍生物，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)，可以消除主动脉瘤形成并预防主动脉破裂首先，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，我们将对脂质介质的协同作用进行定性和定量分析。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-TGF-β1信号传导相关的动脉瘤形成的进展。报告表明，氧化线粒体 (mt) DNA 作为损伤相关模式分子形成 NETs，但在 AAAs 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，我们将测试这些模型的严谨性和可重复性。使用离体主动脉外植体进行动物研究，以确定这些转变是否发生在人体组织中。