mTORC1 activation and alcoholic liver injury

mTORC1 激活与酒精性肝损伤

基本信息

批准号：
8446056
负责人：
MENGWEI ZANG
金额：
$ 24.56万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8446056
关键词：
A Mouse Alcoholic Fatty Liver Alcoholic Liver Diseases Alcoholism Alcohols Apoptosis Attenuated Cells Cessation of life Chronic Cirrhosis Complex Data Deacetylase Development Diabetic mouse Disease Dominant-Negative Mutation Drug Targeting Early Diagnosis Ethanol Fatty Liver Fibrosis Functional disorder GRP78 gene Gene Targeting Gene Transfer Genetic Goals Health Heavy Drinking Hepatic Hepatocyte Homeostasis Hyperglycemia In Vitro Injury Intervention Knowledge Laboratories Lipids Liver Liver diseases Malignant Neoplasms Mediating Metabolism Molecular Molecular Target Mus National Institute on Alcohol Abuse and Alcoholism Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Translocation Obesity Organ Pathogenesis Pathology Pathway interactions Phosphorylation Pilot Projects Play Primary carcinoma of the liver cells Process Protein Kinase Publishing Raptors Relative (related person)Resistance Role SRE-1 binding protein Signal Pathway Signal Transduction Sirolimus Societies Staging Steatohepatitis Stress System TSC1/2 gene Therapeutic Therapeutic Intervention Triglycerides alcohol abuse therapy alcohol effect alcohol exposure base cancer type cell growth regulation chronic alcohol ingestion combat effective therapy endoplasmic reticulum stress feeding in vivo inhibitor/antagonist innovation insight lipid biosynthesis lipine liver injury mTOR protein mouse model novel novel therapeutics outcome forecast overexpression prevent problem drinker programs protein activation response transcription factor treatment strategy

项目摘要

DESCRIPTION (provided by applicant): mTORC1 activation and alcoholic liver injury Key words: alcohol fatty liver, mTORC1, DEPTOR, ER stress, and SREBP-1 Alcoholism is a leading cause of liver disease in Western societies. Hepatic steatosis (fatty liver) is an early and reversible stage of alcoholic liver disease. However, unchecked hepatic steatosis can develop into irreversible steatohepatitis, fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. Alcoholic fatty liver disease (AFLD) is attributed to the activation of endoplasmic reticulum (ER) stress signaling. However, the molecular mechanisms underlying hepatic ER stress in AFLD are not fully understood. Although great progress has been made in the identification of mammalian target of rapamycin complex 1 (mTORC1) pathway components, relatively little is known about the in vivo role of the mTORC1 pathway in alcoholic liver pathophysiology. Our recent studies demonstrate that hepatic inhibition of mTORC1 by the NAD-dependent deacetylase SIRT1 suppresses hepatic ER stress, downregulates lipogenesis, and thereby ameliorates hepatic steatosis in diabetic mice. Exciting preliminary data show that hepatic mTORC1 is activated in chronic binge alcohol-fed mice, which is accompanied by induction of ER stress, activation of lipogenesis, and hepatic steatosis. Importantly, new studies suggest that consistent with mTORC1 activation, hepatic levels of DEPTOR, a newly identified endogenous inhibitor of mTORC1, are reduced in alcohol-fed mice. To better understand the pathogenesis of alcoholic liver disease and develop alternative therapeutic strategies for the disease, our CENTRAL HYPOTHESIS is that mTORC1 plays a key role in alcoholic fatty liver disease by promoting hepatic ER stress and stimulating lipogenesis. Two specific aims are proposed: 1) To characterize the functional and mechanistic role of mTORC1 in alcohol-induced ER stress and lipogenesis in hepatocytes; 2) To determine whether mTORC1 inhibition ameliorates hepatic steatosis and ER stress in mice with alcoholic fatty liver. In response to the NIAAA program (PA-10-094) entitled "stress pathways in alcohol induced organ injury and protection", the proposed studies will determine whether chronic alcohol exposure results in mTORC1 activation via mTORC1 components such as DEPTOR, TSC1/2 or Raptor and thereby accelerates the development of hepatic steatosis and ER stress. In vitro cell-based mechanistic studies as well as in vivo pharmacologic and genetic approaches of manipulating hepatic mTORC1 activity will be utilized. Innovative aspects of these proposed studies include: (1) new insight into mTORC1 as a novel regulator of alcohol-induced ER stress pathways and fatty liver; (2) the novel concept that DEPTOR-dependent inhibition of mTORC1 ameliorates alcoholic fatty liver and liver injury by relieving ER stress and inhibiting lipogenesis; (3) DEPTOR/mTORC1 as new targets for the therapeutic interventions of AFLD and ER stress-related liver diseases such as cancer. Our long-term objective is to elucidate the pathological mechanisms of AFLD, to identify novel molecular targets for intervention at this early and reversible stage of alcoholic liver disease, and to develop a potential marker of AFLD to aid early diagnosis and prognosis.

描述（由申请人提供）：MTORC1激活和酒精性肝损伤关键词：酒精脂肪肝，MTORC1，Deptor，ER压力和SREBP-1酒精中毒是西方社会肝病的主要原因。肝脂肪变性（脂肪肝）是酒精性肝病的早期且可逆的阶段。然而，未检查的肝脂肪变性可以发展为不可逆的脂肪性肝炎，纤维化，肝硬化和最终的肝细胞癌。酒精脂肪肝病（AFLD）归因于内质网（ER）应力信号的激活。然而，尚未完全了解肝ER应力的分子机制。尽管在鉴定雷帕霉素复合物1（MTORC1）途径成分的哺乳动物靶标方面取得了巨大进展，但对于酒精性肝脏病理生理学中MTORC1途径的体内作用却相对较少。我们最近的研究表明，NAD依赖性脱乙酰基酶SIRT1对MTORC1抑制MTORC1可抑制肝ER胁迫，下调脂肪生成，从而改善糖尿病小鼠中的肝脂肪变性。令人兴奋的初步数据表明，肝脏MTORC1在慢性酒精喂养的小鼠中被激活，该小鼠伴随着ER胁迫的诱导，脂肪生成的激活和肝脂肪变性。重要的是，新的研究表明，与MTORC1激活一致，在酒精喂养的小鼠中，肝脏水平是一种新鉴定的MTORC1的内源性抑制剂。为了更好地理解酒精性肝病的发病机理并为该疾病发展替代性治疗策略，我们的中心假设是MTORC1通过促进肝ER应激和刺激脂肪生成来在酒精脂肪肝病中起关键作用。提出了两个具体目的：1）表征MTORC1在酒精诱导的肝细胞中的ER胁迫和脂肪形成中的功能和机械作用； 2）确定MTORC1抑制是否可以改善酒精脂肪肝脏小鼠的肝脂肪变性和ER应激。为了响应NIAAA计划（PA-10-094），标题为“酒精诱导的器官损伤和保护中的应力途径”，提出的研究将确定是否通过MTORC1组件（例如Deptor，TSC1/2或RAPTOR），TSC1/2或RAPTOR以及从而加快了雌性静脉曲张和ER率的发育。将利用基于体外细胞的机械研究以及体内药理和操纵肝MTORC1活性的遗传学方法。这些提出的研究的创新方面包括：（1）对MTORC1的新见解，是酒精引起的ER应激途径和脂肪肝的新型调节剂；（2）通过缓解急诊室应激和抑制脂肪形成，依赖于抑制MTORC1的抑制剂抑制MTORC1的新概念可以改善酒精脂肪肝和肝损伤；（3）Deptor/MTORC1作为AFLD和ER应激相关肝病（例如癌症）治疗干预措施的新靶标。我们的长期目标是阐明AFLD的病理机制，确定在酒精肝病的早期和可逆阶段进行干预的新型分子靶标，并开发出AFLD的潜在标志以帮助早期诊断和预后。