Progerin/PrelaminA诱发早老症的蛋白质组学研究

项目名称： Progerin/PrelaminA诱发早老症的蛋白质组学研究

项目编号： No.81501206

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 钱民先

作者单位： 深圳大学

项目金额： 17.5万元

中文摘要： 儿童早老症HGPS是由LMNA基因突变造成的，其产物早老素(Progerin)如何引发早衰还不清楚，而且至今没有治疗办法。小鼠中敲除Zmpste24引起LaminA前体(PrelaminA)的累积，出现类HGPS症状。我们前期研究发现，LaminA和Progerin/PrelaminA与底物蛋白亲和力呈现显著性差异，导致细胞核内一些重要蛋白的水平、修饰和功能上发生明显改变。本项目将通过差异蛋白质学技术，从细胞和亚细胞两个层面系统研究Zmpste24-/-细胞老化的差异蛋白。利用稳转LaminA/Progerin/PrelaminA的LaminA-/-细胞系，研究三种蛋白的相互作用蛋白组的差异。最后通过生物信息学分析，构建早老相关的蛋白信号网络。本项目预期成果将从根源上揭示早老症的可能诱因；对正常衰老的机制探究起到重要推动作用；为研发抗衰老和衰老相关疾病的药物靶标提供新思路。

中文关键词： 早老症；衰老；细胞衰老；核纤层蛋白A；蛋白质组

英文摘要： Hutchinson-Gilford progeria syndrome (HGPS) is an incurable laminopathy disease caused by the LMNA gene mutation, but how its product progerin initiates premature aging is still unknown. Depleting Zmpste24 in mice leads to the accumulation of Prelamin A and recapitulates many progeroid features found in HGPS patients. Our previous study indicated that LaminA/Progerin/PrelaminA exhibit the distinct protein-binding capacities. As a result, several nuclear proteins are dysregulated in their protein levels, modifications and functions in progeriod cells. Based on the qualitative differential proteomics techniques, the aim of this study is to find out the proteins which are dramatically altered during Zmpste24-/- cell senescence under the cellular and subcellular levels, and to investigate the protein-protein interaction networks of LaminA/Progerin/PrelaminA. Finally we propose to construct the progeria-related network according to bioinformatics analysis. These studies will uncover the orignial inducers of premature aging and extend the understanding of HGPS, suggesting more potential therapeutic strategies for aging-related diseases and also providing evidences for anti-aging.

英文关键词： Progeria;Aging;Cellular senescence;Lamin A;Proteomics