维生素D受体（VDR）及其转录共激活因子在表皮细胞的增殖和分化中扮演重要角色。我们前期发现VDR在角质形成细胞（KCs）增殖/分化不同阶段优势结合不同转录共激活因子（Med1，SRC3等）参与表皮自我更新。Med1主要表达于基底层增殖型KCs，条件性敲除Med1呈现β-catenin信号通路活性上调和TGFβ信号通路活性下调，表皮干细胞（ESCs）的分化走向异常。SRC3则倾向表达于颗粒层分化型KCs，其缺失可导致KCs脂质合成分泌异常，免疫防御功能受损。由此，我们提出了在表皮自我更新及其稳态维持过程中，VDR选择性结合Med1、SRC3形成转录复合物，介导VDR信号及其相关通路（β-catenin，TGFβ）活性，差异化调控下游ESCs自我更新和KCs增殖分化的平衡。本课题深入探究Med1、SRC3精准调控作用机制，为表皮稳态失衡具体环节的特异治疗提供理论依据。

Self-renewal and differentiation of epidermal are strictly regulated by a combination of extrinsic gene signals from the niche as well as intrinsic signal pathways. The vitamin D receptor (VDR) and its co-activators play an essential role in regulating proliferation and differentiation of keratinocytes. The ongoing epidermal renewing process requires a concerted action of transcription factors and coactivator proteins. Previously, we showed the evidence that the sequential proliferation and differentiation of epidermis were directed by coactivators DRIP205 and SRC3 selectively regulating VDR functions. DRIP 205 deletion not only reprogramed hair follicles to epidermal cell fate in epidermal stem cells, but also promoted proliferation and early differentiation of keratinocytes. However, SRC3 deletion resulted in abnormal lipid synthesis and weakened innate immune response triggered by disruption of the barrier. Gene expression profiling indicated that DRIP205 deficiency led to up-regulation of β-catenin signaling and down-regulation of TGFβ signaling. Based on these evidences, we hypothesize that “In ESCs and proliferating KCs, DRIP205 regulates ESCs self-renewal and facilitates the sequential proliferation and differentiation of KCs through modulating signals from β-catenin and TGFβ pathways. In differentiated KCs, SRC3 regulates the expression of molecules required for permeability barrier formation and innate immune response”. In order to determine the mechanism of selective regulation role of DRIP205 and SRC3, we intend to analyze the differential expression profile and select key molecules and signal pathways involved in proliferation and differentiation through Microarray, CHIP-seq, etc. Next, we will use the overexpression/interference model to explore the transcriptional activity modulation of these key factors. Finally, evaluation of epidermal regeneration vitality will confirm the differential role of two coactivators in wound healing process. This project will facilitate our understanding of epidermal renewing programed by DRIP205 and SRC3, and show the potential of specific co-activators as therapeutic targets according to different renewing steps of keratinocytes.