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.

项目概要 人类肥胖是一个与代谢综合征相关的严重的世界性健康问题 以及非酒精性脂肪性肝病 (NAFLD) 的发展，该病可进展为非酒精性脂肪肝 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，大约有 25% 的人口 (1)。对 NASH 患病率的估计是混乱的 由于可靠的非侵入性诊断方法有限，但大约 25% 的患者患有 NAFLD 表现出 NASH (1)。疤痕（肝硬化）和肝纤维化的发展有助于 HCC 是最常见的肝癌，也是癌症相关死亡的第三大原因 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 预计会 成为肝移植的主要适应症 (4)； 2) NAFLD/NASH 相关 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，包括膳食热量 限制和锻炼是当前治疗的关键方面。然而，有效的需求尚未得到满足 药物治疗。目前正在开发几种药物，包括减少 脂肪变性、纠正肠道菌群失调、促进氧化应激防御并抑制纤维化 (5, 6)。 最近的研究表明，氧化应激反应性蛋白激酶 ASK1（ASK1 的成员） MAP3K 组）是治疗 NASH 的有前途的药物靶点 (5, 6)。小分子 Selonsertib 是 ASK1 蛋白激酶活性的有效抑制剂，可减少 NASH 相关的肝纤维化 (7, 8)，这是一个关键因素 疾病进展的决定因素(4)。 Selonsertib 在 NASH 患者中的 2 期试验取得了成功 (7, 8) 导致目前正在进行的 3 期试验（STELLAR 3 和 STELLAR 4） (8)。 阻断 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减少（例如应激激活的 MAPK）。 ASK1 是 表达无处不在。因此，没有关于肝细胞类型的信息。 介导 ASK1 促进的 NASH 特征，包括肝纤维化。 ASK1 可能扮演 在驱动肝纤维化的炎症反应（例如库普弗细胞和其他免疫细胞）中发挥关键作用 （9）。另外，ASK1 可能在促进纤维化的脂肪变性肝细胞中发挥重要作用 (10)。这是 也有可能 ASK1 的关键作用可能是在直接参与肝纤维化的星状细胞中 (11)。 因此，在 NASH 中介导 ASK1 基本功能的相关肝细胞类型尚未明确。 定义的。此外，NASH 发生过程中介导 ASK1 调节的机制并不存在。 明白了。 该提案旨在确定 NASH 发展过程中 ASK1 信号传导的机制。 这项研究的完成将为药物作用机制提供重要的新信息 抑制 ASK1。提出了两个具体目标：1）确定介导该过程的肝细胞类型 ASK1 对 NASH 特征的影响； 2) 确定在 ASK1 期间调节 ASK1 的肝脏机制 NASH 的发展。 该研究计划的总体目标是确定解释的分子机制 ASK1 在 NASH 中的功能。这一目标的实现将增加对 NASH 发展的了解。我们 预计该研究计划的成功完成将导致新的发现 分子机制。这些知识可能代表设计新治疗策略的基础 NASH的治疗，包括合理设计联合疗法。