Treatment for alcoholic liver disease

酒精性肝病的治疗

基本信息

批准号：
8000368
负责人：
Bert J. W. M. Oehlen
金额：
$ 23.85万
依托单位：
ANGION BIOMEDICA CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8000368
关键词：
Adopted Alcohol consumption Alcoholic Hepatitis Alcoholic Liver Diseases Alcoholic liver damage American Animal Model Animals Apoptosis Biochemical Biological Biological Assay Biological Process Biology Biotechnology Blood Vessels CYP1A2 gene CYP2C9 gene CYP2D6 gene CYP3A4 gene Catabolism Cause of Death Cells Cellular Assay Chronic Cicatrix Cirrhosis Clinical Clinical Trials Collaborations Collagen Country Coupling Cytochrome P450 Data Development Disease Drug Kinetics Enzymes Fibrosis Gene Expression Goals Grant Hepatitis C virus Hepatocyte Hepatocyte Growth Factor Histology Human Resources In Vitro Industry Injury to Liver Laboratories Lead Legal patent Ligation Literature Liver Liver Cirrhosis Liver Fibrosis Liver Regeneration Liver diseases Lung Measures Medical Metabolism Microsomes Modeling Molecular Models Monitor Mus Organ Paper Patients Pharmaceutical Chemistry Pharmacologic Substance Phase Portal Pressure Prevention Principal Investigator Property Publishing Pulmonary Emphysema Radiation Oncology Rattus Recombinants Research Research Personnel Resort Retinoids Scientist Screening procedure Series Signal Transduction Small Business Innovation Research Grant Smooth Muscle Actin Staining Method Staging Testing Therapeutic Therapeutic Uses Time Tretinoin United States Work base bile duct clinically relevant connective tissue growth factor design drug discovery drug synthesis effective therapy expectation experience improved in vitro Assay in vivo in vivo Model inhibitor/antagonist liver cell proliferation liver function liver transplantation medical schools mimetics molecular modeling mouse model novel pre-clinical preclinical study prevent problem drinker product development programs public health relevance research study retinoic acid 4-hydroxylase safety study small molecule

项目摘要

DESCRIPTION (provided by applicant): Liver fibrosis is a form of scar formation that is found in almost all patients with chronic injury to the liver. Over time it frequently progresses to cirrhosis, an end-stage lethal disease which is the seventh leading cause of death in the United States and afflicts hundreds of millions of people worldwide. Alcohol intake remains the most important cause of liver cirrhosis in Western countries. Alcoholic liver disease can be divided in various stages of development: (1) mild alcoholic liver injury, (2) steatosis, (3) alcoholic hepatitis, (4) alcoholic liver fibrosis and (5) cirrhosis. Although several pharmacological therapies have been tried in patients with alcoholic liver disease, none of the therapeutics so far has shown consistent improvement in the course of alcoholic liver damage and there remains a major unmet medical need for effective therapies. There is a significant body of evidence implicating a requirement for All Trans Retinoic Acid (ATRA) for normal liver function and in liver regeneration. ATRA administration can prevent and reverse the course of liver fibrosis in animal models. Several studies have shown that inhibition of certain cytochrome P450 enzymes in vivo can boost endogenous ATRA levels and result in retinoid-like activity in dermatological and oncological animal models. The cytochrome P450 enzyme retinoic acid 4-hydroxylase is thought to be the key enzyme involved ATRA catabolism. In our preliminary data, we show that an inhibitor of retinoic acid 4-hydroxylase shows activity in a mouse model of TAA-induced liver fibrosis in mice, thus establishing a novel proof of concept for their potential use as therapeutics for liver fibrosis. Our long-term goal is the development of small molecule inhibitors of retinoic acid 4-hydroxylase as potential therapeutics for alcoholic liver disease. The objective of this application is to identify such inhibitors and evaluate them in two clinically relevant animal models of liver fibrosis. PUBLIC HEALTH RELEVANCE: Liver fibrosis is a form of scar formation that is found in almost all patients with chronic injury to the liver caused by sustained immoderate alcohol consumption. Over time it frequently progresses to cirrhosis, an end- stage lethal disease which is the seventh leading cause of death in the United States and afflicts hundreds of millions of people worldwide. There is no therapeutic that shows consistent improvement in the course of alcoholic liver damage and there remains a major unmet medical need for effective therapies. There is a significant body of evidence implicating a requirement for All Trans Retinoic Acid (ATRA) for normal liver function and in liver regeneration. We intend to develop of small molecule inhibitors of retinoic acid 4- hydroxylase that can elevate the body's ATRA levels as a potential therapeutic for alcoholic liver disease.

描述（由申请人提供）：肝纤维化是一种疤痕形成形式，几乎所有患有慢性肝脏损伤的患者都会发现这种情况。随着时间的推移，它经常发展为肝硬化，这是一种终末期致命疾病，是美国第七大死因，困扰着全世界数亿人。在西方国家，酒精摄入仍然是导致肝硬化的最重要原因。酒精性肝病可分为不同的发展阶段：（1）轻度酒精性肝损伤，（2）脂肪变性，（3）酒精性肝炎，（4）酒精性肝纤维化和（5）肝硬化。尽管已经在酒精性肝病患者中尝试了几种药物疗法，但迄今为止没有一种疗法能够在酒精性肝损伤过程中显示出持续的改善，并且对有效疗法的医疗需求仍然未得到满足。有大量证据表明，正常肝功能和肝再生需要全反式视黄酸 (ATRA)。 ATRA 给药可以预防和逆转动物模型中的肝纤维化进程。多项研究表明，体内抑制某些细胞色素 P450 酶可以提高内源性 ATRA 水平，并在皮肤病学和肿瘤学动物模型中产生类视黄醇样活性。细胞色素 P450 酶视黄酸 4-羟化酶被认为是参与 ATRA 分解代谢的关键酶。在我们的初步数据中，我们表明视黄酸 4-羟化酶抑制剂在 TAA 诱导的小鼠肝纤维化小鼠模型中显示出活性，从而为它们作为肝纤维化治疗的潜在用途提供了新的概念证明。我们的长期目标是开发视黄酸 4-羟化酶的小分子抑制剂作为酒精性肝病的潜在疗法。本申请的目的是鉴定此类抑制剂并在两种临床相关的肝纤维化动物模型中对其进行评估。公共健康相关性：肝纤维化是一种疤痕形成形式，几乎所有因持续过量饮酒而导致肝脏慢性损伤的患者都会出现这种情况。随着时间的推移，它经常发展为肝硬化，这是一种终末期致命疾病，是美国第七大死因，困扰着全世界数亿人。目前还没有一种治疗方法能够持续改善酒精性肝损伤的过程，并且对于有效治疗的医疗需求仍然存在未得到满足的重大问题。有大量证据表明，正常肝功能和肝再生需要全反式视黄酸 (ATRA)。我们打算开发视黄酸 4-羟化酶的小分子抑制剂，它可以提高体内的 ATRA 水平，作为酒精性肝病的潜在治疗方法。