隐性遗传方式儿童早老症患者SASP-like炎症反应病理特征和分子机制研究

儿童早老症与生理性衰老有很多相似特征，包括细胞核变形、组蛋白修饰改变和DNA损伤增多等。我们发现三个隐性遗传方式（LMNA基因R527C纯合突变）儿童早老症家系。对患者外周血转录组分析和皮肤组织免疫组化验证，发现衰老相关的炎症因子IL-6和IL-8高表达。外周血白细胞单细胞测序分析显示巨噬细胞异常，其病理意义不明。为研究异常炎症反应的病理特征和相关分子机制，本研究将利用获得的临床样本鉴定儿童早老症SASP-like（ senescence associated secretory phenotype like）表型的特征，并在LMNA缺失细胞系内研究隐性突变体（LMNA R527C）的功能，同时利用已获得的病人来源iPS细胞分化成巨噬细胞研究其细胞学特征及病理机制，并与生理性衰老作比较。研究结果将有助于确定隐性遗传方式儿童早老症患者对症治疗靶点以及新的抗衰老靶点探索。

Progeria and physiological aging share some similarities including nuclear deformation, histone modification change and DNA damage accumulation . We found three Chinese families with recessive inherited progeria syndrome (linked to the homozygous mutation of R527C in the LMNA gene). Transcriptome analysis of the peripheral blood from the patients showed that the inflammatory factors (IL6 and IL8) related to aging was elevated, and the result of single cell sequencing analysis showed that the patients’ macrophages were abnormal, while their pathological significance was unclear. To investigate the pathological pattern and explore its molecular mechanism, we will identify the characteristics of senescence associated secretory phenotype like (SASP-like) inflammatory response in progeria children with our blood and dermal samples. Next，we will study the function of LMNA R527C mutant in the LMNA knock out cells, and then we will use the patient-derived iPS (induced pluripotent stem cells) cells to study the main pathological characteristics of macrophage by induced differentiation. At last, its pathological significance will compared with those from the physiological aging cases. This research will benefit the therapy target exploring of our recessive inherited progeria cases as well as physiological aging.