Promotion of fatty liver disease by the ASK1 pathway

ASK1 通路促进脂肪肝疾病

• 批准号: 10021651
• 负责人: Roger J Davis
• 金额: $ 54.84万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10021651
• 关键词: Achievement; Caloric Restriction; Cancer Etiology; Cells; Cessation of life; Cicatrix; Cirrhosis; Clinical Trials Design; Combined Modality Therapy; Development; Diagnosis; Diet; Disease Progression; Drug Targeting; Exercise; Exhibits; Fatty Liver; Fibrosis; Goals; Health; Hepatic; Hepatocyte; Human; Immune; Incidence; Inflammation; Inflammatory Response; Intestines; Knowledge; Kupffer Cells; Liver; Liver Fibrosis; Liver diseases; MAP Kinase Gene; MAP3K5 gene; Malignant neoplasm of liver; Mediating; Metabolic syndrome; Methods; Molecular; Mus; Obesity; Obesity associated cancer; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Play; Population; Prevalence; Primary carcinoma of the liver cells; Regulation; Research; Role; Signal Pathway; Signal Transduction; Stains; Stress; Testing; cell type; clinical development; design; drug action; dysbiosis; inhibitor/antagonist; lifestyle intervention; liver transplantation; member; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel therapeutics; phase II trial; phase III trial; programs; small molecule; stellate cell; targeted treatment; treatment strategy; western diet

Project Summary Human obesity represents a serious world-wide health problem that is associated with metabolic syndrome and the development of non-alcoholic fatty liver disease (NAFLD) that can progress to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). The estimated prevalence of NAFLD in the USA is approximately 25% of the population (1). Estimates for the prevalence of NASH are confounded by the limited availability of reliable non-invasive methods for diagnosis, but approximately 25% of patients with NAFLD exhibit NASH (1). The development of scarring (cirrhosis) and hepatic fibrosis contributes to the development of HCC, the most common liver cancer and the 3rd leading cause of cancer-related death in the USA (2, 3). The high incidence of NAFLD/NASH represents a major health problem because: 1) NASH is anticipated to become the leading indication for liver transplantation (4); and 2) NAFLD/NASH-associated HCC is the primary cause of obesity-related cancer death in the USA (4). Lifestyle interventions, including dietary calorie restriction and exercise, are key aspects of current therapy. However, there is an unmet need for effective pharmacotherapy. Several medications are currently under development, including approaches to reduce steatosis, correct intestinal dysbiosis, promote oxidative stress defense, and suppress fibrosis (5, 6). Recent studies have established that the oxidative stress-responsive protein kinase ASK1 (a member of the MAP3K group) is a promising drug target for the treatment of NASH (5, 6). The small molecule Selonsertib is a potent inhibitor of ASK1 protein kinase activity that causes reduced NASH-related hepatic fibrosis (7, 8), a key determinant of disease progression (4). Successful phase 2 trials of Selonsertib in NASH patients (7, 8) have led to phase 3 trials (STELLAR 3 and STELLAR 4) that are currently in progress (8). The mechanism that accounts for the beneficial effects of blocking ASK1 is unknown, but likely involves a reduction in the activation state of down-stream signaling pathways (e.g. stress-activated MAPK). ASK1 is expressed ubiquitously. Consequently, no information is available concerning the hepatic cell type that mediates the ASK1-promoted hallmarks of NASH, including hepatic fibrosis. It is possible that ASK1 plays a key role in an inflammatory response (e.g. in Kupffer cells and other immune cells) that drives hepatic fibrosis (9). Alternatively, ASK1 may play an important role in steatotic hepatocytes that promotes fibrosis (10). It is also possible that the key role of ASK1 may be in stellate cells that are directly involved in hepatic fibrosis (11). The relevant hepatic cell type that mediates the essential function of ASK1 in NASH has therefore not been defined. Moreover, the mechanism that mediates ASK1 regulation during the development of NASH is not understood. This proposal is designed to identify the mechanism of ASK1 signaling during NASH development. Completion of this study will provide important new information concerning the mechanism of action of drugs that inhibit ASK1. Two Specific Aims are proposed: 1) To identify the hepatic cell type that mediates the effects of ASK1 on hallmarks of NASH; and 2) To identify hepatic mechanisms that regulate ASK1 during NASH development. The overall goal of this research program is to identify molecular mechanisms that account for the function of ASK1 in NASH. Achievement of this goal will increase understanding of NASH development. We anticipate that the successful completion of this research program will lead to the identification of new molecular mechanisms. This knowledge may represent a basis for the design of novel therapeutic strategies for the treatment of NASH, including the rational design of combination therapies.

项目摘要 人类肥胖代表了与代谢综合征有关的严重全球健康问题 以及可以发展为非酒精的非酒精性脂肪肝病（NAFLD）的发展 脂肪性肝炎（NASH），肝硬化和肝细胞癌（HCC）。 NAFLD的估计患病率 在美国，约占人口的25％（1）。纳什的患病率的估计是混淆的 可靠的可靠非侵入性方法可用于诊断，但约有25％的患者 NAFLD展览纳什（1）。疤痕（肝硬化）和肝纤维化的发展有助于 HCC的发展，最常见的肝癌和与癌症相关死亡的第三主要原因 美国（2，3）。 NAFLD/NASH的高发病率是一个主要的健康问题，因为：1）NASH预计将 成为肝移植的主要指示（4）； 2）NAFLD/NASH相关的HCC是主要的 美国肥胖相关癌症死亡的原因（4）。生活方式干预，包括饮食卡路里 限制和运动是当前疗法的关键方面。但是，有效的需求未满足 药物治疗。目前正在开发几种药物，包括减少的方法 脂肪变性，正确的肠道营养不良，促进氧化应激防御和抑制纤维化（5，6）。 最近的研究表明，氧化应激反应性蛋白激酶ask1（该成员的成员 MAP3K组）是治疗NASH的有前途的药物靶标（5，6）。小分子Selonsertib是 ASK1蛋白激酶活性的有效抑制剂会导致NASH相关肝纤维化降低（7，8），钥匙 疾病进展的决定因素（4）。 Selonsertib在NASH患者中成功的2期试验（7，8）具有 导致目前正在进行的3阶段试验（Stellar 3和Stellar 4）（8）。 解释阻止Ask1的有益作用的机制尚不清楚，但可能涉及一个 下游信号通路的激活状态的降低（例如应力激活的MAPK）。 Ask1是 无处不在。因此，没有有关肝细胞类型的信息 介导了纳什（Nash）的Ask1促进的标志，包括肝纤维化。 Ask1可能会播放 驱动肝纤维化的炎症反应中的关键作用（例如在库普弗细胞和其他免疫细胞中） （9）。另外，Ask1可能在促进纤维化的脂肪性肝细胞中起重要作用（10）。这是 同样，Ask1的关键作用可能在于直接参与肝纤维化的星状细胞中（11）。 因此，介导NASH中Ask1基本功能的相关肝细胞类型并非 定义。此外，在纳什开发过程中介导ask1调节的机制不是 理解。 该建议旨在确定NASH开发过程中Ask1信号的机制。 这项研究的完成将提供有关药物作用机理的重要新信息 抑制ask1。提出了两个具体目的：1）确定介导的肝细胞类型 Ask1对Nash标志的影响； 2）确定在调节sugs1的肝机制 纳什的发展。 该研究计划的总体目标是确定解释的分子机制 NASH中的Ask1的功能。实现这一目标将增加对纳什发展的理解。我们 预计该研究计划的成功完成将导致新的识别 分子机制。这些知识可能代表设计新型治疗策略的基础 用于纳什的治疗，包括合理的组合疗法。