sEH Inhibition in Alcoholic Liver Disease: A Novel Therapeutic Strategy

酒精性肝病中的 sEH 抑制：一种新的治疗策略

• 批准号: 10473814
• 负责人: Jeffrey B Warner
• 金额: $ 2.48万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10473814
• 关键词: ANXA5 gene; Ablation; Affect; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcohols; Animals; Anti-Inflammatory Agents; Area; Attenuated; Basic Science; Biological; Biological Assay; CXCL1 gene; Cell Death; Cell Line; Cell physiology; Cells; Cellular biology; Cessation of life; Chronic; Clinical; Clinical Research; Data; Development; Disease; Ensure; Environment; Enzyme-Linked Immunosorbent Assay; Epoxide hydrolase; Epoxy Compounds; Ethanol; FDA approved; Fatty Acids; Flow Cytometry; Fostering; Funding; Genetic; Goals; Health; HepG2; Hepatic; Hepatocyte; Histologic; Human; IL6 gene; Immune; Individual; Inflammation; Inflammatory; Interleukin-1 beta; Knock-out; Knockout Mice; Kupffer Cells; Laboratories; Learning; Lipids; Liver; Liver diseases; Medical; Mentors; Modeling; Mus; Neutrophil Infiltration; Oral; Organ; Palmitic Acids; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacology and Toxicology; Phenotype; Physiological; Polyunsaturated Fatty Acids; Positioning Attribute; Predisposition; Prevention; Production; Propidium Diiodide; Research; Research Personnel; Resolution; Resources; Role; Scientist; Slide; Stains; Supervision; TNF gene; Techniques; Testing; Therapeutic; Training; Translational Research; Translations; Travel; Universities; Work; alcohol exposure; bench to bedside; career; career development; career networking; chronic liver disease; cytokine; efficacy evaluation; experience; experimental study; faculty research; feeding; improved; in vivo; inhibitor; lipid mediator; lipidome; lipidomics; liver inflammation; liver injury; macrophage; mouse model; novel therapeutic intervention; novel therapeutics; oral communication; pre-clinical; prevent; recruit; skills; success; translational therapeutics; treatment strategy

Project Summary Alcoholic liver disease (ALD) is the most common liver disease and is responsible for nearly half of all deaths from diseases affecting this organ. Despite this, there remain no FDA-approved treatments for any stage of the disease, highlighting the need for the discovery of new therapies. As an aspiring scientist whose goal is to pursue a career in alcohol-related multi-organ pathology, investigating new therapies for ALD treatment would not only help fill this medical need but also serve as an excellent platform from which to learn how to become a successful scientist. With the help and supervision of my co-mentors Dr. Kirpich (an expert in basic research on ALD) and Dr. McClain (an expert on clinical aspects of the disease) as well as several knowledgeable collaborators, I will investigate soluble epoxide hydrolase (sEH) inhibition as a novel therapeutic strategy for the treatment of ALD using pre-clinical mouse models. This approach has been applied to other inflammatory diseases, but not to ALD, a disease shown by previous work in our group to be characterized by a loss of anti-inflammatory epoxygenated lipids (epoxides), in part due to their rapid degradation by sEH. I have generated substantial preliminary data with an orally-administered sEH inhibitor in a chronic-binge mouse model of ALD that recapitulates human ALD. Through two related, but independent, specific aims proposed in this application I will further assess the efficacy of sEH inhibition and explore its mechanisms of action. Aim 1 will use pharmacological and genetic ablation of sEH to further characterize the effects of sEH inhibition in mouse models of ALD. Aim 2 will describe the mechanistic effects of individual anti-inflammatory epoxides on changes in hepatocyte and immune cell health and function to explain changes seen in vivo. To complete this research, I will follow a detailed training plan laid out for me by my co-mentors and pursue the career goals that I have set for myself. These include, among others, continuing my didactic training in areas relevant to my research, gaining experience in new laboratory techniques, developing effective written and oral communication skills, and building a professional network of scientists. For example, to assess liver injury and changes in cellular function I will learn to read histological liver slides, use enzymatic assays, set up ELISAs, isolate and culture primary hepatocytes and macrophages, and learn flow cytometry. The research environment at the University of Louisville’s state-of- the-art Clinical and Translational Research Building is highly productive and staffed with expert faculty and research personnel willing to help me learn these techniques and advise me as I pursue my training and career goals. My academic department, the Department of Pharmacology & Toxicology, is equally positioned to support my training in the classroom and provide many resources (e.g. travel funds, career development seminars, and new courses) to ensure my success. Collectively, the training and research proposed here will not only fill a significant need for the development of ALD treatments, but will also foster my development from a young scientist to a successful, independent investigator in the field of alcohol-induced organ disease.

项目概要 酒精性肝病 (ALD) 是最常见的肝脏疾病，导致近一半的死亡 免受影响该器官的疾病的影响。尽管如此，FDA 仍然没有批准针对任何阶段的治疗方法。 疾病，凸显了发现新疗法的必要性。作为一名有抱负的科学家，其目标是追求 从事与酒精相关的多器官病理学的职业，研究 ALD 治疗的新疗法不仅 帮助满足这一医疗需求，同时也是学习如何成为成功人士的绝佳平台 科学家。在我的合作导师 Kirpich 博士（ALD 基础研究专家）的帮助和监督下 麦克莱恩博士（该疾病临床方面的专家）以及几位知识渊博的合作者，我将 研究可溶性环氧化物水解酶 (sEH) 抑制作为治疗 ALD 的新型治疗策略 使用临床前小鼠模型。这种方法已应用于其他炎症性疾病，但不适用于 ALD，我们小组之前的工作表明，一种以抗炎作用丧失为特征的疾病 环氧化脂质（环氧化物），部分原因是它们被 sEH 快速降解。我已经产生了大量的 口服 sEH 抑制剂在慢性暴食 ALD 小鼠模型中的初步数据 概括了人类 ALD。通过本申请中提出的两个相关但独立的具体目标，我将 进一步评估sEH抑制的功效并探讨其作用机制。目标1将使用药理学 以及 sEH 的基因消除，以进一步表征 sEH 抑制对 ALD 小鼠模型的影响。目标2 将描述单个抗炎环氧化物对肝细胞变化的机制影响 免疫细胞的健康和功能可以解释体内所见的变化。为了完成这项研究，我将遵循详细的 我的共同导师为我制定了培训计划，并追求我为自己设定的职业目标。这些 除其他外，包括继续在与我的研究相关的领域进行教学培训，获得以下方面的经验： 新的实验室技术，培养有效的书面和口头沟通技巧，并建立 科学家的专业网络。例如，为了评估肝损伤和细胞功能的变化，我将学习 读取组织学肝脏切片、使用酶测定、设置 ELISA、分离和培养原代肝细胞 和巨噬细胞，并学习流式细胞术。路易斯维尔大学的研究环境 最先进的临床和转化研究大楼生产力很高，并配备了专家教师和 研究人员愿意帮助我学习这些技术并在我追求培训和职业生涯时为我提供建议 目标。我的学术部门，药理学和毒理学系，同样有能力支持 我在课堂上接受培训并提供许多资源（例如旅行基金、职业发展研讨会和 新课程）以确保我的成功。总的来说，这里提出的培训和研究不仅将填补 开发 ALD 治疗方法的巨大需求，但也将促进我从小的发展 科学家成为酒精引起的器官疾病领域成功的独立研究者。

项目成果

Human Beta Defensin 2 Ameliorated Alcohol-Associated Liver Disease in Mice.

• DOI: 10.3389/fphys.2021.812882
• 发表时间: 2021
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Warner JB;Larsen IS;Hardesty JE;Song YL;Warner DR;McClain CJ;Sun R;Deng Z;Jensen BAH;Kirpich IA
• 通讯作者: Kirpich IA

Fat-1 Transgenic Mice With Augmented n3-Polyunsaturated Fatty Acids Are Protected From Liver Injury Caused by Acute-On-Chronic Ethanol Administration.

• DOI: 10.3389/fphar.2021.711590
• 发表时间: 2021
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Warner J;Hardesty J;Song Y;Sun R;Deng Z;Xu R;Yin X;Zhang X;McClain C;Warner D;Kirpich I
• 通讯作者: Kirpich I