Gamma-ketoaldehyde scavengers for alcoholic liver disease

γ-酮醛清除剂治疗酒精性肝病

基本信息

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
项目类别：
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

项目摘要

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）：慢性饮酒过量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，但人们对确定其他酒精治疗干预措施有很大兴趣。由于对酒精特异性代谢反应和肝脏病理生理学之间关系的不完全理解，这种进展变得复杂。促炎症状态（ALD 的标志）的诱导似乎取决于这种关系。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，我们寻求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 蛋白加合物的形成会导致免疫原性、炎症和终末器官损伤，因此，应使用选择性 γ-KA 清除剂。 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，这一点已经变得越来越明显。（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 发生反应的试剂，以防止其与细胞蛋白质和其他胺相加成。该提案的目的是检验肝脏 γ-KA 清除会减少的假设。肝损伤 (ALT) 对 ALD 中的先天性和适应性免疫反应有不同的影响我们将确定口服水杨胺对减轻酒精性肝损伤的严重程度和对急性酒精性肝损伤的免疫反应的影响 (2)。天）和慢性（25 天）乙醇喂养的小鼠模型在研究 1 中，我们将检查水杨胺对肝功能（ALT、AST、甘油三酯）以及肝脏和循环 γ-KA、抗的剂量反应影响。当水杨胺与乙醇同时给药时，-γ-KA 抗体滴度以及肝单核细胞浸润我们预计水杨胺将显着减少蛋白质加合形成并改善肝功能。以与适应性免疫反应减弱相一致的方式，包括 T 细胞和 B 细胞增殖、NFκB 激活和 TLR4 信号传导。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。在初次乙醇给药后，水杨胺（以剂量依赖性方式）监测与研究 1 中相同的终点。如果这些研究表明水杨胺可减轻酒精性肝损伤和/或对免疫有不同的影响根据回应，将提出第二阶段研究，以进一步完善水杨胺的作用机制，以用于后续 SBIR 拨款中的产品开发和监管批准。