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The role of AEG-1 in NASH and NASH-HCC

The role of AEG-1 in NASH and NASH-HCC
AEG-1 在 NASH 和 NASH-HCC 中的作用
批准号:
9321495
负责人:
DEVANAND SARKAR
金额:
$34.65万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-07-25 至 2020-06-30

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中文摘要
翻译
摘要 非酒精性脂肪性肝病(NAFLD),从非酒精性脂肪肝(NAFL)延伸到 非酒精性脂肪性肝炎(NASH)是西方世界慢性肝病最常见的原因。 它可导致肝硬变和肝细胞癌,并独立地与 因心血管和肝脏疾病而死亡的风险。食用高脂肪和高胆固醇的饮食, 西式饮食是肥胖和NAFLD的重要决定因素。其分子机制的研究进展 NAFLD逐渐被阐明,导致多种介入方法在临床上的评估 审判。然而,最佳的治疗方法尚未开发出来,需要更深入地了解 非酒精性脂肪肝的分子发病机制、调控该过程的新分子的鉴定及进展 有针对性的治疗方法。我们揭示了星形胶质细胞上调基因-1的一个新角色,也被称为 美贴附素(Mtdh)和抒情,在纳什。一种肝细胞特异性过表达的转基因小鼠 AEG-1(Alb/AEG-1)可发展为自发性NASH。NASH患者AEG-1表达增加 肝脏与正常人相比。另一方面,肝细胞特异性条件性AEG-1基因敲除 小鼠(AEG-1CKOHEP)对高脂饮食(HFD)诱导的脂肪变性表现出显著的抵抗力。这些发现 提示AEG-1可能在调控NASH的发生和发展中起关键作用。从长远来看 本研究的目的是深入了解NASH致病的分子机制 制定有效的治疗策略。眼下的目标是全面审问 AEG-1促进NASH和NASH-HCC的分子机制及对AEG-1抑制作用的评价 NASH的潜在介入策略。我们假设,多个事件,如优先抑制 核受体,脂代谢调节基因的翻译调节和激活 炎症可能参与了AEG-1诱导的NASH,而AEG-1的抑制可能干扰了这些过程 从而抑制NASH的发展和进展。全面的功能性、生化性和 将进行分子分析来解决这些假设。圆满完成拟议中的 研究将深入了解AEG-1促进NASH和HELP的分子机制 建立AEG-1抑制作为治疗NASH和NASH-肝细胞癌的潜在有效策略。因此, 提案具有很高的机械性和翻译性。
英文摘要
Summary Nonalcoholic fatty liver disease (NAFLD), a spectrum extending from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), is the most common cause of chronic liver disease in the Western world. It can lead to cirrhosis and hepatocellular carcinoma (HCC) and is independently associated with an increased risk of death due to cardiovascular and liver diseases. Consumption of high fat and cholesterol containing diet, the Western diet, is an important determinant of obesity and hence NAFLD. The molecular mechanism of NAFLD is gradually being elucidated leading to the evaluation of multiple interventional approaches in clinical trials. However, the optimum therapy is yet to be developed mandating more in-depth understanding of molecular pathogenesis of NAFLD, identification of novel molecules regulating this process and development of targeted therapeutic approaches. We unravel a novel role of Astrocyte elevated gene-1, also known as metadherin (MTDH) and LYRIC, in NASH. A transgenic mouse with hepatocyte-specific overexpression of AEG-1 (Alb/AEG-1) develops spontaneous NASH. NASH patients show increased AEG-1 expression in their liver compared to normal individuals. On the other hand hepatocyte-specific conditional AEG-1 knockout mouse (AEG-1CKOHEP) shows significant resistance to high fat diet (HFD)-induced steatosis. These findings indicate that AEG-1 might play a pivotal role in regulating initiation and progression of NASH. The long term objective of the present proposal is to obtain in-depth understanding of the molecular mechanism of NASH to develop effective therapeutic strategies. The immediate objective is to comprehensively interrogate the molecular mechanism by which AEG-1 promotes NASH and NASH-HCC and evaluate AEG-1 inhibition as a potential interventional strategy for NASH. We hypothesize that multiple events, such as preferential inhibition of nuclear receptors, translational regulation of lipid metabolism regulating genes and activation of inflammation, might contribute to AEG-1-induced NASH and AEG-1 inhibition might interfere with all these events thereby inhibiting development and progression of NASH. A comprehensive functional, biochemical and molecular analyses will be performed to address these hypotheses. Successful completion of the proposed studies will provide in-depth insight into the molecular mechanism by which AEG-1 promotes NASH and help establish AEG-1 inhibition as a potential effective therapeutic strategy for NASH and NASH-HCC. Thus the proposal has high mechanistic and translational significance.
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  • 财政年份:
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  • 负责人:
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  • 依托单位:
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  • 批准号:
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  • 项目类别:
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  • 财政年份:
    2019
  • 负责人:
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  • 依托单位:
A novel role of IGFBP7 in the microenvironment of hepatocellular carcinoma
  • 批准号:
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  • 项目类别:
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海外基金