Development of Gap Junction Inhibition Therapy for Alcoholic Liver Disease

酒精性肝病间隙连接抑制疗法的进展

基本信息

批准号：
8833924
负责人：
RAYMOND T CHUNG
金额：
$ 19.63万
依托单位：
HEPROTECH, 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：
2014-09-20 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8833924
关键词：
Acetaminophen Acute Acute Alcoholic Hepatitis Acute Hepatitis Adrenal Cortex Hormones Affect Alcohol consumption Alcohol-Induced Disorders Alcoholic Hepatitis Alcoholic Intoxication Alcoholic Liver Diseases Alcohols Animal Model Antioxidants Ascites Biochemical Cells Cessation of life Chronic Cirrhosis Clinical Communication Connexins Coupled Critical Care Cytosol Data Development Diet Economic Burden Eligibility Determination Ethanol Fatty Change Fibrosis Frequencies Funding Gap Junctions Genetic Goals Grant Heavy Drinking Hemorrhage Hepatic Hepatocyte Hepatoprotective Agent Hepatotoxicity Hospitalization Immune Immunosuppressive Agents Infection Inflammation Injury Label Lead Liver Liver diseases Mediator of activation protein Medical Metabolism Modeling Morbidity - disease rate Mus National Institute on Alcohol Abuse and Alcoholism Organ Outcome Oxidative Stress Pathogenesis Pathway interactions Patients Pentoxifylline Pharmaceutical Preparations Phase Play Primary carcinoma of the liver cells Program Development Proteins Recurrence Risk Role Scientist Severities Signal Transduction Small Business Innovation Research Grant Staging Steatohepatitis Therapeutic Tissues Transplantation Treatment Efficacy Validation Wild Type Mouse Work acute liver injury base chronic alcohol ingestion chronic liver disease connexin 32 design gastrointestinal infection improved inhibitor/antagonist intercellular communication liver inflammation liver injury liver transplantation meetings mortality mouse model nonalcoholic steatohepatitis novel novel therapeutic intervention outcome forecast pre-clinical preclinical study problem drinker programs public health relevance response small molecule standard of care treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Alcoholic liver disease is a highly prevalent and costly condition affecting millions of people globally. Alcohol results in high morbidity and mortality an is responsible for nearly 4% of all deaths worldwide. Despite the tremendous societal and economic burden, there is no approved therapeutics for alcoholic liver disease. Instead, the standard of care involves off-label administration of nonspecific corticosteroids, immunosuppressants, and antioxidants. There is a desperate need for liver-specific therapeutics that can be used to treat acute and chronic alcoholic liver disease. Heprotech was founded to commercialize therapeutics based on inhibition of gap junction communication in the liver. We have demonstrated that liver-specific gap junctions composed of connexin 32 (Cx32) are essential to the pathogenesis of acute and chronic liver injury. We first showed that inhibitors of Cx32 gap junctions protect and rescue mice from drug-induced hepatotoxicity. Next we found that these Cx32 gap junction inhibitors were protective in diet-induced nonalcoholic steatohepatitis. Most recently, our preliminary results suggest Cx32 gap junctions are also essential for alcohol-induced liver injury. The overall goal of this Phase I SBIR grant is to defin the appropriate clinical context for inhibiting Cx32 gap junctions for protection against alcohol-induced liver injury. In aim 1, we will compare acute and chronic alcohol-induced liver injury in wild type and connexin 32 deficient mice. This will delineate whether the novel Cx32 target is important in acute and/or chronic alcohol-induced liver injury. In aim 2, we will investigate our lead Cx32 small molecule inhibitor in acute and chronic alcohol-induced liver injury. The anticipated outcome of this effort is clarification of whether Cx32 is important in acute injury, chronic injury, or both. Secondly, the proposed work will provide early evidence that small molecule inhibition of Cx32 gap junctions is a viable therapeutic strategy for treatment of alcoholic liver disease. These results will inform the design of focused preclinical studies that will be performed during Phase II of this SBIR program.

描述（由申请人提供）：酒精性肝病是一种非常普遍且代价高昂的疾病，影响着全球数百万人。尽管酒精造成了巨大的社会和经济负担，但其发病率和死亡率却占全球死亡人数的近 4%。目前还没有批准的治疗酒精性肝病的疗法，标准治疗方法是使用非特异性皮质类固醇、免疫抑制剂和抗氧化剂。 Heprotech 的成立是为了将基于抑制肝脏间隙连接通讯的疗法商业化。我们发现，由连接蛋白 32 (Cx32) 组成的肝脏特异性间隙连接对于急性和慢性肝脏的发病机制至关重要。我们首先证明了损伤的抑制剂。 Cx32 间隙连接可保护和拯救小鼠免受药物引起的肝毒性。接下来，我们发现这些 Cx32 间隙连接抑制剂对饮食引起的非酒精性脂肪性肝炎具有保护作用。最近，我们的初步结果表明，Cx32 间隙连接对于酒精引起的肝损伤也至关重要。该 I 期 SBIR 资助的总体目标是确定抑制 Cx32 间隙连接以预防酒精引起的肝损伤的适当临床背景。 1，我们将比较野生型和连接蛋白 32 缺陷小鼠的急性和慢性酒精性肝损伤，这将说明新的 Cx32 靶标在急性和/或慢性酒精性肝损伤中是否重要。研究我们的主要 Cx32 小分子抑制剂在急性和慢性酒精性肝损伤中的作用，这项工作的预期结果是澄清 Cx32 在急性损伤、慢性损伤或两者中是否重要。早期证据表明，小分子抑制 Cx32 间隙连接是治疗酒精性肝病的可行治疗策略。这些结果将为 SBIR 项目第二阶段进行的重点临床前研究的设计提供信息。