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.

项目摘要 酒精性肝病（ALD）是最常见的肝病，几乎是所有死亡的一半 来自影响该器官的疾病。尽管如此，对于任何阶段的任何阶段，仍没有FDA批准的治疗 疾病，强调发现新疗法的需求。作为一个有抱负的科学家，他的目标是追求 从事与酒精有关的多器官病理学的职业，研究ALD治疗的新疗法不仅将 帮助满足这种医疗需求，但也可以作为一个出色的平台，可以从中学习如何成为成功 科学家。在我的联合给出者Kirpich博士（ALD基础研究专家）和 McClain博士（疾病临床方面的专家）以及几个知识渊博的合作者，我将 研究固体环氧化物水解酶（SEH）抑制作用作为治疗ALD的新型治疗策略 使用临床前鼠标模型。这种方法已应用于其他炎症性疾病，但不是 ALD，我们小组以前的工作表现出的一种疾病，其特征是抗炎 环氧脂质（环氧化物）部分是由于SEH的快速降解。我已经产生了大量 在ALD的慢性狂热小鼠模型中，具有口服辅助SEH抑制剂的初步数据 概括了人类ALD。通过在本应用程序中提出的两个相关但独立的特定目标，我将 进一步评估SEH抑制的效率并探索其作用机理。 AIM 1将使用药品。 SEH的遗传消融，以进一步表征SEH抑制在ALD小鼠模型中的影响。目标2 将描述单个抗炎环氧化物对肝细胞变化的机械影响和 免疫细胞健康和功能以解释体内看到的变化。为了完成这项研究，我将遵循详细的 我的副培训计划由我的副主持人为我制定，并追求我为自己设定的职业目标。这些 包括在与我的研究相关的领域中继续进行我的教学培训，获得了经验 新的实验室技术，发展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，要评估肝损伤和细胞功能的变化，我将学习 读取组织学肝载玻片，使用酶试验，建立ELISA，分离和培养原代肝细胞 和巨噬细胞，学习流式细胞仪。路易斯维尔大学的最新研究环境 ART临床和转化研究大楼的生产力很高，配备了专家教职员工和 研究人员愿意帮助我学习这些技术，并在追求培训和职业时为我提供建议 目标。我的学术系，药理学和毒理学系，同样可以支持 我在课堂上的培训并提供许多资源（例如旅行资金，职业发展中心和 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会填补 对ALD治疗的发展非常需要，但也将促进我的发展 科学家是酒精诱发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