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PXR调控代谢稳态并作用于Yes相关蛋白促进肝再生的新机制
结题报告
批准号:
81973392
项目类别:
面上项目
资助金额:
55.0 万元
负责人:
毕惠嫦
依托单位:
学科分类:
药物代谢与药物动力学
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
毕惠嫦
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中文摘要
部分肝切除和肝移植是终末期肝病的最有效治疗手段,如何提高术后肝脏再生能力是急需解决的问题。孕烷X受体(PXR)在机体代谢稳态及肝再生过程起重要作用。我们发现PXR通过调控胆汁酸等代谢稳态抵抗肝损伤,率先发现PXR可激活Yes相关蛋白(YAP)促进良性肝增大(Hepatology, 封面文章)。但PXR促进肝再生的代谢稳态调控特性、PXR激活YAP的分子基础与调节机制尚不清楚。本项目拟在Pxr敲除小鼠、hPXR小鼠、Yap敲除小鼠等模型上确证PXR促进肝再生的作用;运用多组学分析PXR对胆汁酸、脂质、肠道微生物组等代谢稳态的调控特征;运用分子生物学Co-IP、SPR、ITC等方法,揭示PXR对YAP信号轴、共转录因子结合活性等的调节机制,获得PXR与YAP蛋白相互作用的直接证据。最终全面揭示PXR调控代谢稳态并作用于YAP促进肝再生的新机制,为PXR作为肝再生潜在靶点提供新观点和科学证据。
英文摘要
Partial hepatectomy (PHx) and liver transplantation are the most frequently used and effective treatment for end-stage liver diseases. However, the unsatisfied regeneration of the remaining liver tissue usually results in bad prognosis. Therefore, liver regeneration after surgical liver resection is crucial and therapeutic interventions that can promote liver growth after PHx are of clinical importance. Pregnane X receptor (PXR) plays important role in the regulation of metabolism homeostasis and liver regeneration. The yes-associated protein (YAP)-signalling pathway is a critical regulator of liver size and rapidly switches hepatic growth on or off. Recently, we found that PXR and its agonists can regulate the homeostasis of bile acids to promote liver regeneration after toxin-induced injury or a partial hepatectomy. For the first time, we found that PXR can also promote liver enlargement via activation of YAP signaling. However, the molecular mechanisms between PXR and YAP, and the key role of metabolism homeostasis in liver regeneration remains unknown. In this study, the effect of PXR activation on liver regeneration will be evaluated in several strains of genetically-modified mice and animal models such as Pxr-null, PXR-humanized and PHx mice. Metabolomic, targeted metabolomics on bile acids, lipidomic, and gut microbiota assay will be performed to reveal the true endpoint and biomarkers for this biological event. Furthermore, the effect of PXR on the YAP up-stream and down-stream axis, protein-protein interactions between PXR and YAP will be proved by kinds of molecular biochemistry methods, co-IP, GST-pull down, SPR assays etc. Yap null mice will be further used to investigate whether the PXR-induced liver regeneration depends on activation of the YAP pathway. Taken together, this study will clearly demonstrate a novel function of PXR in promoting liver regeneration via activation of the YAP signalling pathway and regulation of metabolism homeostasis. These studies will have implications for understanding the physiological functions of PXR and may provide a clinically relevant argument for using PXR as a potential therapeutic target for promoting hepatic development and liver repair.
期刊论文列表
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专利列表
DOI:10.1038/s41401-021-00793-3
发表时间:2021-12
期刊:Acta Pharmacologica Sinica
影响因子:8.2
作者:Dong Huang;Ying-yuan Zhao;Rui-min Wang;Wei Li;Fang-yu Yuan;Xue-long Yan;Xiao Yang;G. Tang-
通讯作者:Dong Huang;Ying-yuan Zhao;Rui-min Wang;Wei Li;Fang-yu Yuan;Xue-long Yan;Xiao Yang;G. Tang-
DOI:10.1016/j.livres.2020.03.001
发表时间:2020-06
期刊:Liver Research
影响因子:--
作者:Xiao Yang;F. Gonzalez;Min Huang;H. Bi
通讯作者:Xiao Yang;F. Gonzalez;Min Huang;H. Bi
DOI:10.1038/s41401-021-00633-4
发表时间:2021-03
期刊:Acta Pharmacologica Sinica
影响因子:8.2
作者:Xin-peng Yao;Tingying Jiao;Yiming Jiang;Shi-cheng Fan;Ying-yuan Zhao;Xiao Yang;Yue Gao;Fei Li
通讯作者:Xin-peng Yao;Tingying Jiao;Yiming Jiang;Shi-cheng Fan;Ying-yuan Zhao;Xiao Yang;Yue Gao;Fei Li
DOI:10.1124/dmd.120.000061
发表时间:2020-09-01
期刊:DRUG METABOLISM AND DISPOSITION
影响因子:3.9
作者:Jiao, Tingying;Yao, Xinpeng;Bi, Huichang
通讯作者:Bi, Huichang
DOI:10.1016/j.phymed.2021.153520
发表时间:2021-02
期刊:Phytomedicine : international journal of phytotherapy and phytopharmacology
影响因子:--
作者:Ying-yuan Zhao;Xin-peng Yao;Tingying Jiao;Jianing Tian;Yue Gao;Shi-cheng Fan;Pan Chen;Yiming Jiang-Yi
通讯作者:Ying-yuan Zhao;Xin-peng Yao;Tingying Jiao;Jianing Tian;Yue Gao;Shi-cheng Fan;Pan Chen;Yiming Jiang-Yi
国内基金
海外基金