核膜下异染色质损失是生理性和过早性衰老个体成纤维细胞的一个显著特征。然而，异染色质损失的原因及其在细胞衰老中的作用尚不明确。本申请项目以一种过早老化性疾病——哈钦森-吉尔福德儿童早老症(HGPS)为研究对象，旨在阐明参与染色质结构调节的HMGA家族蛋白及其介导的染色质结构改变在HGPS细胞衰老中的作用及机制。我们前期的工作发现，在progerin过表达模拟的HGPS细胞中，HMGA表达水平降低，其靶基因纺锤体组装检验点核心组分BubR1表达下调，而能够抑制HMGA基因表达的miR-26a等多个miRNA水平升高。本项目拟在以上工作的基础上，在细胞、组织和个体水平明确HMGA在HGPS细胞衰老和异染色质损失中的作用及机制；阐明HGPS细胞中HMGA低表达的miRNA网络调控机制。本项目的完成将为HGPS的发病机制提供新的理论依据，同时为揭示生理性衰老的分子机制提供新的线索。

Loss of heterochromatin is a hallmark of normal and premature aging cell, however, the reason and the role of loss of heterochromatin in cellular senescence is largely unknown. The project is based on Hutchinson–Gilford progeria syndrome (HGPS) cellular senescence, aimed at illuminating the role and mechanism of HMGA, which involved in regulation of chromatin structure, in regulation of chromatin structure in HGPS cellular senescence. Our previous work found that HMGA proteins were downregulated in HGPS cells, while multiple miRNAs including miR-26a were upregulated in HGPS cells. Meanwhile, HMGA target gene BubR1 was also downregulated in HGPS cells. Based on the previous research, from the level of cell, tissue and animal in vivo, we intend to definite the role and mechanism of HMGA in HGPS cellular senescence and loss of heterochromatin, explore the miRNA regulation network of HMGA in HGPS cells. This study will provide further insights into the mechanism of HGPS, also be valuable in the exploration of the mechanism of physiologic senescence.