去乙酰化酶SIRT1在前体mRNA可变剪切中的作用及其生理病理效应研究
结题报告
批准号:
31970691
项目类别:
面上项目
资助金额:
58.0 万元
负责人:
张胜萍
依托单位:
学科分类:
细胞衰老、死亡及自噬
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
张胜萍
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中文摘要
糖尿病视网膜病变是成人失明的首要病因。RHO基因突变可致视网膜细胞死亡,但对该基因的表达调控研究非常匮乏。申请人发现SIRT1敲除小鼠视网膜细胞死亡并伴随RHO前体mRNA错误剪切;SIRT1与RHO的剪切因子PRPF31结合并调控其去乙酰化,SIRT1敲低可引发RHO错误剪切;Ins2Akita糖尿病小鼠RHO出现错误剪切和PRPF31高乙酰化。另外,我们模拟糖尿病过氧化压力实验发现,过氧化可刺激SIRT1磷酸化并伴随RHO mRNA错误剪切和PRPF31乙酰化增高。我们将研究正常和压力状态下,SIRT1如何调控PRPF31乙酰化-RHO mRNA可变剪切-视网膜细胞死亡这一轴线及其在视网膜病变中的作用,并在动物层面探讨SIRT1激活剂及AAV-SIRT1对糖尿病视网膜RHO mRNA错误剪切、细胞死亡和病变抑制的可行性。本研究将为mRNA可变剪切调控及视网膜病变提供新理论和干预途径。
英文摘要
Diabetic retinopathy is the leading cause of blindness among working people in developed countries. It has been well established that some RHO mutants can induce retinal cell death, but the regulatory mechanism of its expression is largely unknown. We observed enhanced cell death and mis-splicing of rhodopsin (RHO) pre-mRNA in the retina of SIRT1 KO mouse. We also demonstrated SIRT1 interacts and deacetylates PRPF31, which plays important role in the splicing of RHO pre-mRNA, and SIRT1 knockdown induced mis-splicing of RHO pre-mRNA. In the retina of diabetic Ins2Akita mice, PRPF31 acetylation and RHO pre-mRNA mis-splicing were both enhanced. Oxidative stress has been implicated in the pathophysiology of diabetic nephropathy, and can downregulate SIRT1 expression and its deacetylase activity. We also observed that, oxidative stress induces SIRT1 phosphorylation, and concomitantly the PRPF31 acetylation and RHO pre-mRNA mis-splicing. Thus, in this proposal, we plan to investigate how SIRT1 regulates the PRPF31 acetylation-RHO pre-mRNA splicing-retinal cell death pathway under normal and stress conditions. Moreover, we will also treat the diabetic mouse with SIRT1 activators and AAV-SIRT1 virus, with aims to restrain the diabetic retinopathy related RHO pre-mRNA mis-splicing, cell death, and thus inhibite the diabetic retinopathy progression. This study will provide new insights for pre-mRNA alternative splicing regulation, and provide new strategy for the intervention and treatment of diabetic retinopathy.
期刊论文列表
专著列表
科研奖励列表
会议论文列表
专利列表
The ATM and ATR kinases regulate centrosome clustering and tumor recurrence by targeting KIFC1 phosphorylation.
ATM 和 ATR 激酶通过靶向 KIFC1 磷酸化来调节中心体聚类和肿瘤复发。
DOI:10.1038/s41467-020-20208-x
发表时间:2021-01-04
期刊:Nature communications
影响因子:16.6
作者:Fan G;Sun L;Meng L;Hu C;Wang X;Shi Z;Hu C;Han Y;Yang Q;Cao L;Zhang X;Zhang Y;Song X;Xia S;He B;Zhang S;Wang C
通讯作者:Wang C
蛋白质相变在铜死亡抵抗中的作用和机制研究
  • 批准号:
    --
  • 项目类别:
    面上项目
  • 资助金额:
    --
  • 批准年份:
    2024
  • 负责人:
    张胜萍
  • 依托单位:
国内基金
海外基金