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Role of Soluble Epoxide Hydrolase in Alcohol-Associated Liver Disease

可溶性环氧化物水解酶在酒精相关性肝病中的作用

基本信息

批准号：
10389013
负责人：
IRINA A. KIRPICH
金额：
$ 42.21万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10389013
关键词：
Ablation Alcohols Animal Model Animals Anti-Inflammatory Agents Attenuated Biological Markers Blood Blood specimen CXCL1 gene Cirrhosis Dietary Supplementation Disease Disease Progression Enzymes Epoxide hydrolase Epoxy Compounds Ethanol Etiology Evaluation FDA approved Fatty Acids Fatty Liver Fatty acid glycerol esters Fibrosis Foundations Genetic Glycols Goals Health Care Costs Heavy Drinking Hepatic Hepatitis Hepatocyte Human In Vitro Individual Infection Inflammation Inflammatory Injury Kidney Lipids Liver Liver diseases Lung Mediating Mediator of activation protein Messenger RNA Metabolic Diseases Metabolism Morbidity - disease rate Mus N-3 polyunsaturated fatty acid Names Neutrophil Infiltration Obesity Organ failure PPAR gamma Pathogenesis Pathology Patients Pharmacology Phenotype Plasma Play Prevention Preventive Production Property Resolution Role Severity of illness Steatohepatitis Testing Therapeutic Transgenic Organisms Treatment Efficacy Whole Blood attenuation base chemokine cytokine effective therapy in vivo inhibitor liver injury macrophage monocyte mortality neutrophil non-alcoholic fatty liver disease novel novel therapeutic intervention novel therapeutics organ regeneration peripheral blood preservation prevent receptor systemic inflammatory response therapeutic effectiveness therapeutic evaluation therapeutic target therapeutically effective tissue regeneration

项目摘要

Alcohol-associated liver disease (ALD) is a spectrum of liver disorders ranging from hepatic steatosis to steatohepatitis with varying degrees of fibrosis and cirrhosis. ALD is a major cause of morbidity, mortality, and health care costs in the US and worldwide. However, there is no FDA-approved therapy for any stage of ALD. There is also an incomplete understanding of the mechanisms and mediators of disease progression and severity. Soluble epoxide hydrolase (s-EH), a master enzyme that regulates the metabolism of endogenous bioactive lipids (e.g., epoxy-fatty acids, Ep-FAs), has recently been recognized as an emerging therapeutic target in multiple diseases. The overall goal of this project is to test the therapeutic efficacy of s-EH inhibition at different stages of ALD severity, and to provide a mechanistic foundation for using s-EH inhibition as a novel therapy for alcohol-induced liver pathology. Aim 1. To test the therapeutic effectiveness of s-EH inhibition as a novel therapeutic strategy for ALD. We will: i) test whether modulation of s-EH activity by pharmacological inhibition or s-EH (Ephx2) genetic ablation can effectively attenuate or prevent EtOH-induced liver injury in experimental ALD; ii) evaluate whether s-EH inhibition leads to stabilization of blood and liver Ep-FAs; and iii) correlate changes in Ep-FA levels with markers of liver injury. Systemic and targeted liver-specific delivery of s- EH inhibitors (t-TUCB and TPPU), and WT and Ephx2 -/- mice (global and liver-specific) will be used in multiple animal models of ALD, which produce different stages of disease severity and which recapitulate different features of human ALD. This allows for a rigorous evaluation of the effects of s-EH inhibition at different stages of ALD severity. Treatment and prevention paradigms will be applied. Aim 2. To explore mechanism(s) underlying the beneficial effects of s-EH inhibition in experimental ALD. We will determine whether Ep-FA stabilization mediated by s-EH inhibition plays a critical role in attenuation of EtOH-induced liver injury. We will test whether n3 vs n6 Ep-FAs exert a greater beneficial effect by enhancing M2 macrophage polarization, increasing a pro-restorative/pro-resolving macrophage phenotype, and by Ep-FAs-PPARγ-CXCL1-mediated reduction of neutrophil infiltration. s-EH inhibitors, WT, transgenic fat-1 mice (which endogenously convert n6 PUFAs to n3 PUFAs), and hepatocyte-specific Pparγ-/- mice will be used. In vivo and in vitro studies will be performed. Aim 3. To evaluate EtOH-induced alterations in s-EH and Ep-FAs in human ALD. Utilizing de- identified human plasma and whole blood samples, we will: i) evaluate alterations in plasma Ep-FAs and establish relationships between biomarkers of liver injury and systemic inflammation in patients with alcohol- associated hepatitis (AH); ii) determine the effects of n3-PUFA dietary supplementation on plasma Ep-FAs in heavy drinking individuals; and iii) test whether s-EH inhibition and Ep-FAs (including both n3 and n6 Ep-FAs) can effectively decrease basal and LPS-stimulated pro-inflammatory cytokine production in whole blood and peripheral blood monocytes obtained from AH patients.

酒精相关性肝病 (ALD) 是一系列肝脏疾病，范围从肝脂肪变性到脂肪性肝炎伴有不同程度的纤维化和肝硬化。 ALD 是发病率、死亡率和死亡率的主要原因美国和全球的医疗保健费用。然而，FDA 尚未批准针对 ALD 任何阶段的治疗方法。对疾病进展和疾病进展的机制和介质的了解也不完全。严重程度。可溶性环氧化物水解酶（s-EH），调节内源性物质代谢的主酶生物活性脂质（例如环氧脂肪酸、Ep-FA）最近被认为是一个新兴的治疗靶点在多种疾病中。该项目的总体目标是测试 s-EH 抑制的治疗效果不同阶段的 ALD 严重程度，并为使用 s-EH 抑制作为新的治疗方法提供机制基础治疗酒精引起的肝脏病理。目的 1. 测试 s-EH 抑制的治疗效果作为一种新的 ALD 治疗策略。我们将： i) 测试是否通过药理学调节 s-EH 活性抑制或 s-EH (Ephx2) 基因消融可以有效减轻或预防 EtOH 引起的肝损伤实验性原子层沉积； ii) 评估 s-EH 抑制是否会导致血液和肝脏 Ep-FA 稳定；和三）将 Ep-FA 水平的变化与肝损伤标志物相关联。系统性和靶向性肝脏特异性递送 s- EH 抑制剂（t-TUCB 和 TPPU）以及 WT 和 Ephx2 -/- 小鼠（整体和肝脏特异性）将用于多种治疗 ALD 动物模型，产生不同阶段的疾病严重程度并概括不同的人类 ALD 的特征。这样可以对不同阶段 s-EH 抑制的效果进行严格评估 ALD 严重程度。将应用治疗和预防范例。目标 2. 探索机制 s-EH 抑制在实验性 ALD 中的有益作用的基础。我们将确定 Ep-FA 是否 s-EH 抑制介导的稳定作用在减轻 EtOH 诱导的肝损伤中发挥着关键作用。我们将测试 n3 与 n6 Ep-FA 是否通过增强 M2 巨噬细胞极化发挥更大的有益作用，增加促恢复/促消退巨噬细胞表型，并通过 Ep-FAs-PPARγ-CXCL1 介导中性粒细胞浸润减少。 s-EH 抑制剂，WT，转基因 fat-1 小鼠（内源性转化 n6 将使用 PUFA 至 n3 PUFA）和肝细胞特异性 Pparγ-/- 小鼠。体内和体外研究将执行。目标 3. 评估 EtOH 诱导的人类 ALD 中 s-EH 和 Ep-FA 的变化。利用去确定了人类血浆和全血样本后，我们将： i) 评估血浆 Ep-FA 的变化和建立酒精患者肝损伤生物标志物与全身炎症之间的关系相关性肝炎（AH）； ii) 确定 n3-PUFA 膳食补充剂对血浆 Ep-FA 的影响酗酒者； iii) 测试是否s-EH抑制和Ep-FAs（包括n3和n6 Ep-FAs）可以有效减少全血中基础和 LPS 刺激的促炎细胞因子的产生，外周血单核细胞取自 AH 患者。