Inflammation Resolving Lipid Mediators: Novel Therapy for Alcohol AssociatedLiver Disease

消炎脂质介质：酒精相关性肝病的新疗法

• 批准号: 10590047
• 负责人: CRAIG J. MCCLAIN
• 金额: --
• 依托单位: LOUISVILLE VA MEDICAL MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590047
• 关键词: Alcohol abuse; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic beverage heavy drinker; Alcohols; Animal Model; Arachidonate 15-Lipoxygenase; Attenuated; Biological Response Modifiers; Breast; COVID-19 pandemic; Cessation of life; Chronic; Cirrhosis; Clinical; Colon; Cytokine Signaling; Data; Diet; Dietary Fats; Dietary Intervention; Disease; Disease Progression; Down-Regulation; Epidemic; Ethanol; Experimental Animal Model; FAT gene; FDA approved; FPR2 gene; Future; GPR32 gene; Health; Health Care Costs; Hepatic; Hepatitis; Hepatitis C; Hepatocellular Damage; Homeostasis; Host Defense; Human; Immune; Immune response; Immunity; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Intestinal permeability; Intestines; Linoleic Acids; Liver diseases; Macrophage; Mediating; Mediator; Modeling; Molecular; Mus; Nuclear; Nutritional; Organoids; PTGS2 gene; Pathogenesis; Pathway interactions; Patients; Phagocytosis; Phenotype; Plasma; Play; Polyunsaturated Fatty Acids; Production; Prognosis; Prostate; Research; Resolution; Rodent; Role; Sampling; Severities; Severity of illness; Signal Transduction; Survivors; System; Testing; Therapeutic Agents; Time; Tissues; Transcript; Transgenic Organisms; Translating; United States Department of Veterans Affairs; Untranslated RNA; Veterans; Whole Blood; attenuation; cancer type; cyclooxygenase 1; cytokine; gut inflammation; gut microbiota; gut-liver axis; improved; in vivo evaluation; intestinal barrier; intestinal injury; lipid mediator; liver inflammation; liver injury; military veteran; monocyte; mortality; new therapeutic target; novel; novel therapeutics; preclinical study; receptor; repaired; systemic inflammatory response; tissue repair

Alcohol-associated liver disease (ALD) is a major health problem in the US (especially in the Veteran population) and alcohol abuse/ALD has increased dramatically during the COVID pandemic. In spite of the magnitude of this problem, there is no FDA-approved therapy for any stage of ALD. In addition, the mechanisms and regulators of disease progression and severity are incompletely understood. Dietary fats play an important interactive role with alcohol consumption in ALD pathogenesis, however, the role of specific n3 polyunsaturated fatty acids (PUFAs) in ALD are not well defined. Our central hypothesis is that n3 PUFAs are beneficial in ALD, in part, via n3-PUFA-derived pro-resolving mediators, which facilitate inflammation resolution, improvement in the gut-liver axis, and subsequent attenuation of liver injury. We propose that n3 PUFA- derived resolvin D1 (RvD1) is a potential therapeutic agent in ALD acting via RvD1-FPR2-NEAT1 signaling to suppress pro-inflammatory cytokines and to promote repair of hepatocellular damage, in part, via enhancement of pro-restorative macrophages. We postulate that compromised inflammation resolution due to impaired RvD1 production/signaling is a critical nutritional factor contributing to the progression and severity of ALD/alcohol- associated hepatitis (AH) in humans. The Specific Aims of the proposal are: Aim 1: determine the role and molecular mechanism(s) underlying n3 PUFA and RvD1 beneficial effects in EtOH-induced liver injury and resolution of inflammation associated with ALD. We will determine whether beneficial effects occur through an increase in n3-PUFA-derived specialized pro-resolving mediators (SPMs), and RvD1-FPR2 and Neat1-mediated suppression of pro-inflammatory cytokine signaling and reprogramming pro-inflammatory macrophages to a pro- restorative phenotype. Wild Type (WT), Fpr2-/-, Neat1-/-, and transgenic fat-1 mice (which are able to endogenously convert n6 to n3 PUFAs) will be used in this Aim. Aim 2: examine the role n3-PUFAs and RvD1 in maintaining gut barrier integrity, and in the resolution of intestinal inflammation in experimental ALD. We will: i) test in vivo, in animal models, and in vitro, in intestinal organoid culture, whether n3 PUFAs or RvD1 improve intestinal barrier damage by attenuating intestinal immune dysregulation; ii) test in vivo whether disruption of the RvD1-FPR2 axis exacerbates, while blocking Neat1 signaling attenuates, intestinal inflammation and alterations in the gut barrier integrity; and iii) determine the contribution of the gut microbiota to the beneficial effects of n3 PUFAs and RvD1 in experimental ALD. Aim 3: translate and extend our findings in animal models to human ALD. Utilizing human samples obtained from Veteran AH patients, we will: i) examine plasma SPM levels and correlate plasma SPM levels with markers of liver injury, systemic inflammation, and intestinal permeability; ii) evaluate basal and LPS-inducible SPM production in whole blood (ex-vivo system) and blood monocytes; and iii) test whether RvD1 improves the phagocytosis/efferocytosis capacity of blood monocytes, and determine if disruption of the RvD1-FPR2 axis will enhance, while silencing of NEAT1 will decrease, pro-inflammatory cytokine expression in human monocytes. These three aims will define both untested novel mechanisms for ALD initiation/progression as well as potential novel therapy that could be rapidly initiated for Veterans with ALD.

酒精相关性肝病（ALD）是美国的一个主要健康问题（特别是在退伍军人中）。 人口）及酒精滥用/酒精依赖症的情况在COVID大流行期间急剧增加。尽管有 由于这个问题的严重性，没有FDA批准的用于ALD任何阶段的治疗。此外，机制 并且疾病进展和严重性的调节因子还不完全清楚。膳食脂肪在 酒精消耗在ALD发病机制中的相互作用，然而，特定的n3多不饱和脂肪酸的作用， ALD中的脂肪酸（PUFA）没有很好的定义。我们的中心假设是n3 PUFA有益于 ALD部分通过n3-PUFA衍生的促消退介质，其促进炎症消退， 肠-肝轴的改善和随后的肝损伤的减轻。我们建议n3 PUFA- 衍生的消退素D1（RvD 1）是ALD中的潜在治疗剂，其通过RvD 1-FPR 2-NEAT 1信号传导作用于 抑制促炎细胞因子并部分通过增强 促进修复的巨噬细胞我们假设由于RvD 1受损而导致的炎症消退 生产/信号是一个关键的营养因素，有助于ALD/酒精的进展和严重性， 人类相关肝炎（AH）。该提案的具体目标是：目标1：确定作用， n3 PUFA和RvD 1在EtOH诱导的肝损伤中的有益作用的分子机制， 缓解与ALD相关的炎症。我们将通过以下方式确定是否会产生有益效果： n3-PUFA衍生的特异性促消退介质（SPM）增加，RvD 1-FPR 2和Neat 1介导的 抑制促炎细胞因子信号传导和将促炎巨噬细胞重编程为促炎细胞因子， 恢复表型野生型（WT）、Fpr 2-/-、Neat 1-/-和转基因fat-1小鼠（其能够 将n6内源性转化为n3 PUFA）。目的2：检查n3-PUFAs和RvD 1的作用 在维持肠道屏障完整性，并在实验性ALD的肠道炎症的决议。我们将： i）在体内、在动物模型中和在体外、在肠类器官培养物中测试n3 PUFA或RvD 1是否改善了 ii）在体内测试是否破坏了肠屏障， RvD 1-FPR 2轴恶化，而阻断Neat 1信号转导减弱肠道炎症和改变 iii）确定肠道微生物群对N3有益作用的贡献 实验性酒精中毒中的PUFA和RvD 1。目标3：将我们在动物模型中的发现转化并扩展到人类 ALD。利用从退伍军人AH患者获得的人样品，我们将：i）检查血浆SPM水平， 将血浆SPM水平与肝损伤、全身性炎症和肠通透性的标志物相关联; ii） 评价全血（离体系统）和血液单核细胞中的基础和LPS诱导的SPM产生;和 iii）测试RvDl是否改善血液单核细胞的吞噬/吞噬能力，并确定RvDl是否改善血液单核细胞的吞噬/吞噬能力。 RvD 1-FPR 2轴的破坏将增强，而NEAT 1的沉默将减少， 人单核细胞中的细胞因子表达。这三个目标将定义ALD的两个未经测试的新机制 启动/进展以及潜在的新疗法，可以迅速启动退伍军人与ALD。