Nutritional Transcriptomics Approach for the Role of Astaxanthin in Liver Fibrosis

虾青素在肝纤维化中作用的营养转录组学方法

• 批准号: 9037916
• 负责人: Ji-Young Lee
• 金额: $ 34.72万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9037916
• 关键词: Apoptosis; Biological Models; Candidate Disease Gene; Cells; Cicatrix; Cirrhosis; Clinic; Development; Diet; Etiology; Experimental Models; Extracellular Matrix Proteins; Fibrosis; Gene Expression Profile; Gene Targeting; Genes; Hepatic Stellate Cell; Histone Deacetylase; Human; In Vitro; Knockout Mice; Knowledge; Liver; Liver Fibrosis; Mediating; Mediator of activation protein; Molecular; Mouse Cell Line; Mus; Myofibroblast; Nutritional; Pathogenesis; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Play; Prevention; Prevention therapy; Primary biliary cirrhosis; Primary carcinoma of the liver cells; Process; Public Health; Regulation; Role; Specimen; Staging; Testing; Therapeutic; Xanthophylls; astaxanthine; chronic liver disease; cytokine; genome-wide; in vivo; liver injury; mouse model; novel; prevent; public health relevance; transcriptomics

 DESCRIPTION (provided by applicant): Liver fibrosis is a scarring process that occurs in most of chronic liver diseases. While liver fibrosis can progress to cirrhosis, it is also reversible. Hepatic stellate cells (HSC) play a crucial role in the development and regression of liver fibrosis. During liver injury, quiescent HSC (qHSC) transdifferentiate to myofibroblasts-like activated HSC (aHSC) that produce extracellular matrix proteins and fibrogenic cytokines. During the regression of liver fibrosis, aHSC are removed by apoptosis or inactivated to a quiescent stage. A half of aHSC have been shown to be inactivated during the regression of liver fibrosis. Therefore, regulation of HSC activation/inactivation is a critical target for the prevention/therapy of liver fibrosis. No anti-fibrotic drugs have yet reached the clinic to date. Or limited knowledge of molecular players critically involved in the development or regression of liver fibrosis has been a primary challenge to the development of an effective anti-fibrotic therapy. Our previous studies using various experimental model systems have demonstrated novel findings that histone deacetylase 9 (HDAC9) play a critical role in the regulation of HSC activation; and astaxanthin (ASTX), a xanthophyll carotenoid, inhibits the fibrogenic action of HDAC9. Importantly, the inhibitory effect of ASTX on HDAC9 does not only prevent HSC activation, but reverts aHSC to a quiescent state, suggesting that ASTX may be able to prevent and regress liver fibrosis. To expand our novel observations, identifying gene signatures associated with liver fibrosis that are under the regulation of HDAC9 and ASTX is critical. The OBJECTIVES of this project are to conduct a genome- wide transcriptome analysis to identify new HDAC9-regulated genes by which the anti-fibrogenic effect of ASTX is mediated, and to corroborate the findings in vivo as well as in human liver specimens of various chronic liver diseases. As guided by our strong preliminary observations, we establish CENTRAL HYPOTHESIS that HDAC9 is a pro-fibrotic mediator involved in the activation of qHSC. By repressing HDAC9, ASTX exerts an anti-fibrotic action, preventing HSC activation and facilitating the inactivation of aHSC in the liver. The inhibitory effect of ASTX on HDAC9, in turn will prevent the development of liver fibrosis and regress the fibrotic condition, ultimately preventing the progression of fibrosis to cirrhosis. This hypothesis is supported by our strong preliminary results and we will test the hypothesis by pursuing the following three SPECIFIC AIMS: 1) To perform genome-wide transcriptome analysis to identify fibrogenic molecular mediators regulated by HDAC9 and ASTX in HSC from wild-type (WT) and Hdac9 knockout mice; 2) to determine the effect of HDAC9 and ASTX on the prevention and regression of liver fibrosis in vivo using two fibrosis mouse models, i.e., WT and Hdac9 knockout mice with CCl4-induced or diet-induced liver fibrosis; and 3) to validate candidate fibrotic genes in HSC regulated by HDAC9 and ASTX in vivo and in human fibrotic livers. Large IMPACT on public health is anticipated upon completion of this study as the new gene targets will be identified to establish effective and safe strategies for the prevention and therapy for human chronic liver diseases manifesting fibrosis.

 描述（由申请人提供）：肝纤维化是一种瘢痕形成过程，发生在大多数慢性肝病中。虽然肝纤维化可以进展为肝硬化，但它也是可逆的。肝星状细胞（HSC）在肝纤维化的发生和消退中起着至关重要的作用。在肝损伤期间，静止HSC（qHSC）转分化为肌成纤维细胞样激活的HSC（aHSC），其产生细胞外基质蛋白和纤维化细胞因子。在肝纤维化消退期间，aHSC通过凋亡被去除或失活至静止阶段。在肝纤维化消退过程中，一半的aHSC被灭活。因此，调控HSC活化/失活是预防/治疗肝纤维化的关键目标。到目前为止，还没有抗纤维化药物到达诊所。或有限的知识，关键参与肝纤维化的发展或消退的分子球员一直是一个主要的挑战，发展一个有效的抗纤维化治疗。我们先前使用各种实验模型系统的研究已经证明了新的发现，即组蛋白脱乙酰酶9（HDAC 9）在HSC活化的调节中起关键作用;并且虾青素（ASTX），一种叶黄素类胡萝卜素，抑制HDAC 9的纤维化作用。重要的是，ASTX对HDAC 9的抑制作用不仅阻止HSC活化，而且使aHSC恢复到静止状态，这表明ASTX可能能够预防和逆转肝纤维化。为了扩大我们的新观察，识别与HDAC 9和ASTX调控下的肝纤维化相关的基因特征至关重要。该项目的主要目的是进行全基因组转录组分析，以鉴定新的HDAC 9调节基因，通过该基因介导ASTX的抗纤维化作用，并证实体内以及各种慢性肝病的人类肝脏标本中的发现。在我们强有力的初步观察的指导下，我们建立了中心假设，即HDAC 9是参与qHSC激活的促纤维化介质。通过抑制HDAC 9，ASTX发挥抗纤维化作用，防止HSC活化并促进肝脏中aHSC的失活。ASTX对HDAC 9的抑制作用反过来将防止肝纤维化的发展并使纤维化状况消退，最终防止纤维化进展为肝硬化。这一假设得到了我们强有力的初步结果的支持，我们将通过以下三个具体目标来检验这一假设：1）进行全基因组转录组分析以鉴定野生型（WT）和Hdac 9敲除小鼠HSC中由HDAC 9和ASTX调节的纤维化分子介质; 2）使用两种纤维化小鼠模型，即，WT和Hdac 9敲除小鼠的CCl 4诱导或饮食诱导的肝纤维化;和3）验证在体内和在人纤维化肝脏中由HDAC 9和ASTX调节的HSC中的候选纤维化基因。本研究完成后，预计将对公共卫生产生重大影响，因为将确定新的基因靶点，以建立有效和安全的策略，用于预防和治疗表现为纤维化的人类慢性肝病。