衰老是指机体随着年龄的增长而发生的组织结构、生理功能等退行性变化的过程，成体干细胞的老化及衰竭是造成该现象的主要原因之一。我们拟结合基因编辑以及人类干细胞技术，深入探讨NF-kB信号通路对人类成体干细胞稳态与衰老的影响及其作用机制。通过在人多能干细胞水平特异性修饰或敲除NF-kB信号通路关键调控基因，并利用定向诱导分化技术，获得NF-kB内源组成型激活与NF-kB缺失的组织特异性的人类成体干细胞。通过细胞生物学，分子生物学，组学分析等手段，从关键基因、信号通路、蛋白相互作用网络到基因表达调控等多个视角研究NF-kB信号通路对干细胞衰老的影响及作用机制。预期成果可为因干细胞功能紊乱而引起的老年疾病的研究提供重要理论依据。

Aging is referred as a progressive degenerative process in physiological integrity, function maintenance of the body. The accumulation of stem cell damage and exhaustion has been identified as the major contribution of aging. Here we combined gene-editing and human stem cell technologies to expound the regulatory roles of NF-kB in human adult stem cell homeostasis during aging. To create an unbiased human stem cell model, we generate the P65 or ikB knock-out human embryonic stem cell lines followed by specifically direct differentiation into adult stem cells. P65 and ikB are two major regulatory proteins of NF-kB pathway, their knock-out lines separately represent as “loss of function” and “gain of function” of NF-kB pathway. By combination of transcriptomic and proteomic analyses, we expect to reveal NF-kB–associated molecular signaling networks in different types of human adult stem cells during aging. The implement of the project will provide theoretical basis to a better understanding of the mechanism of human adult stem cell aging