内质网钙通道ITPR2调控的钙信号在细胞衰老中具有重要作用，我们先前报道细胞核受体RXRA靶向抑制ITPR2及下游钙信号并延缓人成纤维细胞的衰老；然而作为转录招募因子，RXRA在细胞衰老中协同其他因子抑制ITPR2的机理尚不清楚。因此，本研究旨在进一步探索RXRA在衰老中的自身调控机制。项目首先利用siRNA库筛选ITPR2的转录调控因子并结合免疫共沉淀等技术，初步发现锌指蛋白ZBTB17与RXRA相互作用并抑制ITPR2的表达。然后利用敲低、过表达和钙成像检测等技术，明确ZBTB17是否通过RXRA抑制ITPR2及下游钙信号并延缓细胞衰老。最后在体内稳定过表达ZBTB17并下调RXRA，以确定ZBTB17是否依赖RXRA延缓机体老化。本结果将揭示ZBTB17协同RXRA抑制ITPR2及下游钙信号并延缓衰老的具体机制，有助于提高我们对衰老分子机理的理解并为衰老及相关疾病的防治提供理论靶点。

The Endoplasmic Reticulum (ER) calcium release channel Inositol 1,4,5-Trisphosphate Receptor, Type 2 (ITPR2) has emerged as a key mediator during cellular senescence. Besides, we have recently identified the nuclear receptor Retinoid X Receptor Alpha (RXRA) as a new senescence repressor through directly inhibiting ITPR2 and its downstream calcium signaling. However, as a transcriptional recruiter, the mechanism by which RXRA inhibits ITPR2 during cellular senescence remains unclear. Therefore, the aim of this project is to investigate the self-regulation mechanism of RXRA during senescence. We firstly analyzed the regulation of ITPR2 based on a siRNA screen targeting 160 transcriptional regulators in human fibroblasts, and the Zinc Finger And BTB Domain Containing 17 (ZBTB17) was primarily identified as an ITPR2 inhibitor and was further proved as a RXRA cooperator by Co-Immunoprecipitation (Co-IP). Then we will verify whether ZBTB17 repress cellular senescence via RXRA or not through strategies such as genes knockdown, overexpression as well as calcium imaging for live cells. Lastly, we will confirm this cascade with the help of in vivo experiments through injecting virus containing knockdown of RXRA to mice with constant overexpressing ZBTB17. Our research will reveal the mechanism of ZBTB17 modulating senescence through cooperating with RXRA. This work could improve our understanding of cellular senescence and the role of calcium signaling in this process, and should thus contributing to the explanation of aging and aging associated diseases.