Project 1 - Yan Li, PhD

项目1 - 李岩博士

• 批准号: 10377896
• 负责人: Yan Li
• 金额: $ 21.52万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-10 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10377896
• 关键词: Adipose tissue; Agonist; Attention; Biological Process; Cell Adhesion Molecules; Cells; Centers of Research Excellence; Chimeric Proteins; Cirrhosis; Development; Disease Progression; Doctor of Philosophy; Early treatment; Endocrine; Enzymes; FDA approved; FGF19 gene; FGF21 gene; Fatty Liver; Feces; Feedback; Fibroblast Growth Factor; Goals; Hepatocyte; Hormones; Human; Incidence; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Interleukin-17; Interleukins; Investigation; Knock-out; Knowledge; Lesion; Link; Lipids; Lipolysis; Liver; Malignant neoplasm of liver; Mediating; Metabolic; Metabolic Diseases; Metabolism; Molecular Target; Mus; Mutation; Neurons; Nonesterified Fatty Acids; Obesity; Orthologous Gene; Pathway interactions; Patients; Pharmacology; Phase; Phase II Clinical Trials; Plasma; Population; Preventive; Primary carcinoma of the liver cells; Production; Proteomics; Publishing; Research; Risk Factors; Signal Transduction; TLR4 gene; TP53 gene; Testing; Toxicology; Variant; advanced disease; anti-cancer; blood glucose regulation; cancer stem cell; carcinogenesis; clinical application; efficacy evaluation; fatty acid metabolism; fibroblast growth factor receptor 4; high risk; ileum; insight; lipid metabolism; liver cancer model; liver injury; markov model; metabolomics; negative affect; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel strategies; novel therapeutic intervention; novel therapeutics; overexpression; polypeptide; prevent; therapeutic target; therapeutically effective; tumor; uptake

Non-alcoholic steatohepatitis (NASH), a potential precursor of hepatocellular carcinoma (HCC), currently has no FDA-approved treatment. Recent studies of fibroblast growth factor (FGF)19 and FGF21 on metabolism suggest that endocrine FGFs and their derivatives carry great potential as novel therapeutics to treat metabolic condi- tions, including NASH. The Pegylated FGF21 (MS-986036) and FGF19 agonist (NGM282) have been studied in clinical phase II trials. Our preliminary studies show that the lack of FGF21 accelerates steatohepatities pro- gression and HCC transformation. Overexpression of FGF19/FGF receptor 4 significantly correlated with epithe- lial cell adhesion molecule (EpCAM) as a marker of hepatic cancer stem cells within the fatty liver-steatosis- cirrhosis-HCC sequence in patients. Recent studies indicated that FGF21 down-regulates the Th17-IL-17 axis, suppresses NF-κB but activates p53 pathways, which are the critical anti-cancer mechanism(s). However, there is no evidence demonstrating the specific anticancer effect of FGF21 on the NASH associated HCC. It is also unknown whether FGF21 could negatively affect the Th17-IL-17 axis and the carcinogenetic signaling to abolish the carcinogenetic transformation from NASH to HCC. Our central hypothesis is that FGF21 and FGF15/19 prevent NASH-HCC through, in turn, controlling lipolysis, clearing excessive FFAs, and inhibiting the IL- 17A signaling mediated inflammation and carcinogenesis. The hypothesis will be tested in the following Specific Aims. Aim 1: Investigate lipid metabolic disorder and IL-17A mediated inflammation during NASH-HCC transition. Establishing NASH-HCC mice to, 1) determine FFA pools (plasma, adipose, liver and feces) and FA metabolites by metabolomics; 2) determine metabolic enzymes and components of IL-17A signaling by targeting proteomics. Aim 2: Evaluate the efficacy of FGF21 (LY2405319) and FGF19 (NGM282) against NASH-HCC transition. Administrating LY2405319/NGM282 in NASH-HCC mice to, 1) evaluate NASH score, HCC incidence, hepatic injury and HCC lesion; 3) determine IL-17A-mediated inflammation/carcinogenesis and tumor-initiating cells. Aim 3: Explore the preventive mechanism(s) of FGF21/FGF15/19 against NASH-HCC transition. Repro- ducing NASH-HCC in FGF21 knockout (KO), FGF15KO and IL-17A mutation mice to investigate the feedback loop of FGF21/FGF15/19-IL-17A on molecular target(s) linking to carcinogenetic pathways. The importance of this proposal is: 1) to explore pharmacological use of FGF21/FGF15/19 against the NASH-HCC transition; and 2) to reveal therapeutic targets and mechanism(s), especially the IL-17 signaling linked carcinogenetic pathways, during NASH-HCC transition.

非酒精性脂肪性肝炎（NASH）是肝细胞癌（HCC）的潜在前体，目前还没有 FDA批准的治疗方法最近关于成纤维细胞生长因子（FGF）19和FGF 21对代谢的研究表明， 内分泌FGF及其衍生物作为治疗代谢性疾病新疗法具有巨大潜力， 包括NASH。已经研究了聚乙二醇化的FGF 21（MS-986036）和FGF 19激动剂（NGM 282）， 在临床II期试验中。我们的初步研究表明，缺乏FGF 21会加速脂肪肝， 回归和HCC转化。FGF 19/FGF受体4的过度表达与上皮细胞增殖显著相关。 肝细胞粘附分子（EpCAM）作为脂肪肝-脂肪变性内肝癌干细胞的标志物- 患者的腹水-HCC序列。最近的研究表明，FGF 21下调Th 17-IL-17轴， 抑制NF-κB，但激活p53通路，这是关键的抗癌机制。但 没有证据表明FGF 21对NASH相关HCC的特异性抗癌作用。也是 目前尚不清楚FGF 21是否会对Th 17-IL-17轴和致癌信号产生负面影响， 从NASH到HCC的致癌转化。我们的中心假设是FGF 21和FGF 15/19 预防NASH-HCC，依次通过控制脂解，清除过量的FFA，并抑制IL-10， 17 A信号传导介导的炎症和致癌作用。该假设将在下面进行检验 具体目标。目的1：探讨NASH-HCC过程中脂质代谢紊乱和IL-17 A介导的炎症反应 过渡建立NASH-HCC小鼠以：1）测定FFA池（血浆、脂肪、肝脏和粪便）和FA 通过代谢组学确定代谢酶和IL-17 A信号传导的组分， 蛋白质组学目的2：评价FGF 21（LY 2405319）和FGF 19（NGM 282）对NASH-HCC的疗效 过渡在NASH-HCC小鼠中施用LY 2405319/NGM 282以：1）评价NASH评分、HCC发病率， 肝损伤和HCC病变; 3）确定IL-17 A介导炎症/致癌作用和肿瘤起始 细胞目的3：探讨FGF 21/FGF 15/19对NASH-HCC转化的预防机制。复制- 在FGF 21敲除（KO）、FGF 15敲除和IL-17 A突变小鼠中诱导NASH-HCC以研究反馈 FGF 21/FGF 15/19-IL-17 A在与致癌途径连接的分子靶点上的环。的重要性 该建议是：1）探索FGF 21/FGF 15/19针对NASH-HCC转变的药理学用途;和 2)揭示治疗靶点和机制，特别是IL-17信号转导相关的致癌途径， 在NASH-HCC转变期间。