HBV非经典x蛋白通过p53依赖性途径介导肝细胞衰老在肝衰竭中的作用

批准号:
81971310
项目类别:
面上项目
资助金额:
55.0 万元
负责人:
赵英仁
依托单位:
学科分类:
衰老机制与调控
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
赵英仁
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中文摘要
肝衰竭病死率高,内科救治未获突破。尽管发病机制尚未明确,但肝细胞增殖障碍和高炎症状态是其重要特征。我国肝衰竭主要病因仍是HBV感染,我们前期发现非经典x(HBwx)与经典x不同,前者导致细胞周期S期阻滞、促前炎症介质分泌,这既是细胞衰老的特征,也是肝衰竭的表现;还发现HBwx在肝衰竭组织异常表达、主要分布在胞核、与p53结合。据此提出HBwx诱导p53入核导致肝细胞衰老(细胞周期阻滞+炎症表型)促进肝衰竭的假说。本研究拟采用短截蛋白技术在分子水平定位HBwx/p53作用结构域;在细胞模型明确HBwx对p53核浆分布调控及促细胞周期阻滞、炎症表型释放的作用,基因编辑敲除p53以验证HBwx诱导肝细胞衰老和炎症表型是否依赖p53;在HBwx+小鼠研究其诱导p53入核、促细胞衰老的机制;在人体肝组织验证该通路。本项目有助于阐明新基因HBwx功能,探索其促细胞衰老作用,丰富HBV-肝衰竭发病机制。
英文摘要
Liver failure is a life-threatening clinical syndrome with high mortality. In China, the predominant cause is hepatitis B virus (HBV) infection. No breakthrough has been made in medical treatment, and the precise mechanism underlying liver failure remains unclear. Liver failure (herein referred to as subacute and acute-on-chronic liver failure) characterized impaired liver regeneration and dysregulated inflammation, which is directly led to unfavorable prognosis..In the previous funding cycle, our lab generated a substantial amount of data characterized the molecular function of HBwx, which was different from the classical x protein. Further explorative studies shown a robust HBwx staining in liver tissues from patients with liver failure. Secondly, HBwx expressing cells were cell-cycle arrested at S phase. Senescence is characterized by irreversible cell-cycle arrest. Thirdly, p53 protein, a hub in cell-cycle arrest and senescence, directly binds to HBwx. To further explore the differences function on HBx and HBwx on cell cycle, we isolated nuclei from HBx or HBwx expressing cells to characterize HBx/HBwx subcellular localization. It was demonstrated that HBx is cytoplasm sequestration, whileas HBwx is predominantly in nuclei. The cellular localization of p53 is importance for its function. For example, p53 cytoplasm sequestration by binding to cytoplasmic HBx linked to cell proliferation and liver cancer,relocation of p53 to nucleus is desirable to inhibit cells growth.. We hypothesis that HBwx functions in liver failure through p53 mediated senescence and senescence associated secretory phenotype(SASP). Our central hypothesis will be tested by four specific aims: (1)Map the binding domains required to mediate interacting each other; explorer whether the binding ability will be strengthen or attenuated in the presence/absence of senescent factors or inhibitors. In an extension of this aim, we shall test if the interaction of HBwx and p53 is necessary for both senescence and SASP. (2)We will elucidate whether HBwx induced senescence and SASP play a role in liver failure. We will also explore the mechanism of HBwx by testing cell-cycle arrest, senescent signaling, by specific inhibitors or genetic manipulating related gene with CRISPR/Cas9 gene editing system.(3) We will utilize genetically manipulated mice expressing HBwx in hepatocytes to explore HBwx function in liver failure mouse model, test the hypothesis that HBwx induced senescence and SASP contributed to liver failure, and elucidate the molecular pathway by which HBwx inducing senescence and inflammation. (4) To confirm the HBwx-p53- senescence-SASP pathway by testing the related molecular in fresh liver tissue from patients diagnosed with liver failure. This contribution will uncover molecular function of HBwx in senescence and inflammation, re-evaluate inflammatory function of hepatocytes, better our understanding of the molecular basis and be widely applicable to other senotherapies.
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DOI:10.1080/2162402x.2024.2304963
发表时间:2024
期刊:Oncoimmunology
影响因子:7.2
作者:
通讯作者:
DOI:10.1007/s10753-023-01941-z
发表时间:2023-12-21
期刊:INFLAMMATION
影响因子:5.1
作者:Wu,Yuchao;Ni,Tianzhi;Liu,Jinfeng
通讯作者:Liu,Jinfeng
DOI:10.1016/j.jcmgh.2023.10.012
发表时间:2024
期刊:CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
影响因子:7.2
作者:Fu, Shan;Ni, Tianzhi;Zhang, Mengmeng;Ren, Danfeng;Feng, Yali;Yao, Naijuan;Zhang, Xiaoli;Wang, Ruojing;Xu, Weicheng;Yang, Nan;Yang, Yuan;He, Yingli;Zhao, Yingren;Liu, Jinfeng
通讯作者:Liu, Jinfeng
DOI:10.1002/jhbp.1112
发表时间:2022-12
期刊:Journal of hepato-biliary-pancreatic sciences
影响因子:3
作者:
通讯作者:
HBV前X基因致癌作用的体内外研究
- 批准号:30671862
- 项目类别:面上项目
- 资助金额:30.0万元
- 批准年份:2006
- 负责人:赵英仁
- 依托单位:
CIITA基因多态性与家族聚集性HBV感染慢性化关系研究
- 批准号:30270597
- 项目类别:面上项目
- 资助金额:23.0万元
- 批准年份:2002
- 负责人:赵英仁
- 依托单位:
国内基金
海外基金
