Gamma-ketoaldehyde scavengers for alcoholic liver disease

γ-酮醛清除剂治疗酒精性肝病

• 批准号: 8834691
• 负责人: John A Rathmacher
• 金额: $ 15.16万
• 依托单位: METABOLIC TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-25 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8834691
• 关键词: 2-hydroxybenzylamine; Abstinence; Acetaldehyde; Acute; Address; Adrenal Cortex Hormones; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcohols; Aldehydes; American Society of Hematology; Amines; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; B Cell Proliferation; Benzylamines; Binding; Biochemical; Buckwheat; CD4 Positive T Lymphocytes; CD8B1 gene; Chronic; Cirrhosis; Comorbidity; Complement; DNA; Data; Disease Outcome; Dose; Endotoxins; Epidemiology; Ethanol; Ethanol Metabolism; F2-Isoprostanes; Free Radicals; Functional disorder; Gene Expression; Goals; Grant; Health; Healthcare; Hepatic; Hepatitis; Histologic; Immune; Immune response; Incidence; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury to Liver; Interruption; Isoprostanes; Knowledge; Lactams; Lead; Lipid Peroxidation; Lipids; Lipopolysaccharides; Liver; Liver diseases; Lysine; Malignant neoplasm of liver; Malondialdehyde; Marketing; Metabolic; Modeling; Monitor; Mus; Nutraceutical; Obesity; Organ; Pathogenesis; Pathway interactions; Patients; Pentoxifylline; Pharmaceutical Preparations; Phase; Play; Prednisone; Prevalence; Process; Production; Prostaglandin-Endoperoxide Synthase; Proteins; Rattus; Reaction; Reactive Oxygen Species; Reporting; Research Personnel; Risk Factors; Role; Serum; Severities; Signal Transduction; Small Business Innovation Research Grant; T-Lymphocyte; Technology; Testing; Therapeutic Intervention; Time Study; TimeLine; Treatment Cost; Triglycerides; Viral hepatitis; adduct; alcohol exposure; burden of illness; chronic liver disease; crosslink; design; feeding; immunogenic; immunogenicity; improved; interest; ketoaldehyde; link protein; liver function; liver injury; monocyte; mouse model; phase 2 study; prevent; problem drinker; product development; response; response to injury; success; toll-like receptor 4

DESCRIPTION (provided by applicant): Chronic alcohol overconsumption is the third largest risk factor for disease burden worldwide and is a frequent comorbidity of liver disease and cancer. While abstinence is a cornerstone of treatment, there is considerable interest in identifying other therapeutic interventions for alcoholic liver disease (ALD). Such advances are complicated by an incomplete understanding of the relationship between alcohol-specific metabolic responses and liver pathophysiology. The induction of a pro-inflammatory state, hallmark of ALD, appears to depend upon the unfavorable interplay among reactive oxygen species (ROS), protein adduct formation, and both the innate and adaptive immune responses. In this SBIR Phase I project, we hypothesize that the formation of highly reactive compounds, termed γ-ketoaldehydes (γ-KA), formed primarily by non-enzymatic free radical catalyzed lipid peroxidation and secondarily by cyclooxygenases (COX) activity, is crucial for ethanol-induced liver injury. γ-KAs react very rapidly with protein lysyl residues to form stable lactam adducts which elicit specific immune reactions. The formation of these γ-KA-protein adducts lead to immunogenicity, inflammation and end-organ damage. Hence, the use of selective scavengers of γ-KAs should lead to interruption of the pathogenic inflammatory responses leading to improvements in ALD. It has become increasingly evident that the interplay among ROS, lipid peroxidation and immune responses is important in the pathogenesis of ALD. Our collaborator (LJ Roberts, MD) has identified Salicylamine as an agent that rapidly and preferentially reacts with γ-KAs to prevent their adduction to cellular proteins and other amines. The goal of this proposal is to test the hypothesis that hepatic γ-KA scavenging will reduce liver injury (ALT) and have differential effects on innate and adaptive immune responses in ALD. We will determine the effects of orally administered Salicylamine on reducing the severity of alcohol liver injury an on immune responses in acute (2 day) and chronic (25 day) ethanol-fed mouse models. In study 1, we will examine the dose-response effects of Salicylamine on liver function (ALT, AST, triglyceride), as well as hepatic and circulating γ-KAs, anti-γ-KA antibody titers as well as livr monocyte infiltration when Salicylamine is administered concurrent with ethanol. We anticipate Salicylamine will significantly reduce protein adduction formation and improve liver function in a manner that is concordant with diminished adaptive immune responses including T and B cell proliferation, NFκB activation and TLR4 signaling. In study 2 we will employ the same 2 day and 25 day ethanol-fed mouse models to induce liver injury, but will administer Salicylamine (in a dose-dependent manner) after the primary ethanol administration then monitor the same endpoints as in study 1. If these studies demonstrate that Salicylamine reduces alcohol liver injury and/or have a differential effect on immune responses, Phase II studies will be proposed to further refine the mechanisms of action of Salicylamine desired for product development and regulatory approvals in a subsequent SBIR grant.

描述（由申请人提供）：长期过量饮酒是全球疾病负担的第三大危险因素，也是肝病和癌症的常见合并症。虽然戒酒是治疗的基石，但人们对确定酒精性肝病 (ALD) 的其他治疗干预措施非常感兴趣。由于对酒精特异性代谢反应与肝脏病理生理学之间关系的不完全理解，这些进展变得更加复杂。促炎症状态的诱导（ALD 的标志）似乎取决于活性氧 (ROS)、蛋白质加合物形成以及先天性和适应性免疫反应之间的不利相互作用。在这个 SBIR 第一阶段项目中，我们假设高活性化合物的形成，称为 γ-酮醛 (γ-KA)，主要由非酶自由基催化的脂质过氧化作用形成，其次由环氧合酶 (COX) 活性形成，对于乙醇诱导的肝损伤至关重要。 γ-KA 与蛋白质赖氨酰残基反应非常迅速，形成稳定的内酰胺加合物，从而引发特异性免疫反应。这些 γ-KA 蛋白加合物的形成导致免疫原性、炎症和终末器官损伤。因此，使用选择性 γ-KA 清除剂应该会中断致病性炎症反应，从而改善 ALD。越来越明显的是，ROS、脂质过氧化和免疫反应之间的相互作用在 ALD 的发病机制中发挥着重要作用。我们的合作者（LJ Roberts，医学博士）已确定水杨胺是一种能够快速且优先地与 γ-KA 发生反应以防止其与细胞蛋白质和其他胺相加合的试剂。该提案的目的是检验肝脏 γ-KA 清除将减少肝损伤 (ALT) 并对 ALD 中的先天性和适应性免疫反应产生不同影响的假设。我们将确定口服水杨胺对减轻急性（2 天）和慢性（25 天）乙醇喂养小鼠模型中酒精性肝损伤严重程度和免疫反应的影响。在研究 1 中，我们将检查当水杨明与乙醇同时给药时，水杨明对肝功能（ALT、AST、甘油三酯）以及肝脏和循环 γ-KA、抗 γ-KA 抗体滴度以及 Livr 单核细胞浸润的剂量反应影响。我们预计水杨胺将显着减少蛋白质加成形成并改善肝功能，其方式与适应性免疫反应（包括 T 和 B 细胞增殖、NFκB 激活和 TLR4 信号传导）减弱相一致。在研究 2 中，我们将采用相同的 2 天和 25 天乙醇喂养小鼠模型来诱导肝损伤，但将在初次乙醇给药后施用水杨胺（以剂量依赖性方式），然后监测与研究 1 中相同的终点。如果这些研究证明水杨胺减少酒精性肝损伤和/或对免疫反应有不同的影响，将提出 II 期研究以进一步完善水杨胺的作用机制 后续 SBIR 拨款中的产品开发和监管批准所需。