VDR及其转录辅激活因子MED1对表皮干细胞的调控机制研究

批准号:
81573075
项目类别:
面上项目
资助金额:
60.0 万元
负责人:
胡立志
依托单位:
学科分类:
H1206.皮肤病学研究新技术与新方法
结题年份:
2019
批准年份:
2015
项目状态:
已结题
项目参与者:
白云峰、朱云娟、任继玲、陈苓苓、高菲、章婧、朱晓龙、孙越
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中文摘要
维生素D受体(VDR)及其转录辅激活子MED1在角质形成细胞的增殖和分化中扮演重要角色。角质细胞培养体系中发现MED1可与VDR结合促进细胞分化,但在体内实验中发现MED1的功能不完全依赖于VDR。当我们特异性敲除小鼠表皮MED1(MED1KO),皮肤毛囊更新周期增强,而VDRKO的更新周期受到阻碍。创伤愈合实验发现MED1KO组愈合速度加快,而VDRKO组创口愈合速度减慢。表皮干细胞在毛囊周期循环、创伤修复中起着关键性作用。提示了VDR、MED1对表皮干细胞具有不同的调控作用。后期研究发现MED1KO小鼠角质细胞中β-catenin靶基因表达量显著升高,而VDRKO小鼠与其相反。从而提出了VDR、MED1与β-catenin相互作用可决定表皮干细胞的细胞命运。本课题将探究VDR,MED1,β-catenin三者对表皮干细胞功能的调控机制,为皮肤创伤修复及皮肤肿瘤等疾病的临床治疗提供新思路。
英文摘要
The vitamin D receptor (VDR) plays an essential role in regulating proliferation and differentiation of keratinocytes. The function of VDR is mediated by transcriptional co-regulators. During the previous funding cycle we examined the potential for different coregulators of the VDR to regulate its different functions in the IFE and HF. MED1 anchors the Mediator complex to VDR and other nuclear hormone receptors. In cultured keratinocytes MED1 was required for both calcium and 1,25(OH)2D/VDR to inhibit proliferation and promote differentiation, acting as expected as a coactivator for VDR. In vivo mice lacking VDR in their keratinocytes are blocked in their HF cycling, but mice lacking MED1 in their keratinocytes have an accelerated rate of HF cycling, although the terminal differentiation of the hair follicle to produce the shaft is lost. In the epidermis mice lacking VDR in their keratinocytes have a decreased proliferative response to wounding, and migration to close the wound is delayed. The opposite is true in mice lacking MED1. At the molecular level, deletion of VDR reduces β-catenin signaling, whereas MED1 deletion increases it. Th β-catenin pathway plays an essential role in activation of the bulge stem cells of the HF and the subsequent proliferation of the SC progeny in the hair germ and outer root sheath during anagen. The role of β-catenin signaling in the activation/function of SC in the epidermis is less clear, although recent studies suggest that it may have a similar role in these cells. In this project our focus will be on the role of VDR and MED1 in regulating epidermal SC function, whether differences in this regulation can be attributed to differences in β-catenin signaling, and whether such differences can explain important physiologic functions like wound healing and skin cancer.
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。表皮角质形成细胞是皮肤稳态维持的主要功能细胞,探究其有序增殖、分化、凋亡、和保护性屏障功能对于皮肤稳态建立和维持理解具有重要意义。我们研究发现,转录共激活因子MED1主要表达于增殖活性KCs,在表皮的增殖、分化中起主要调控角色;MED1缺失可导致VDR介导下β-catenin、TFGβ等多条信号通路活性改变,我们提出Med1可选择性结合VDR形成转录复合物,调控VDR介导下的β-catenin及TGFβ信号通路活性,差异化调控下游增殖、分化、物理屏障和免疫屏障相关靶基因有序表达,以维持皮肤稳态。我们首先评估Med1敲除小鼠皮肤稳态功能变化水平,并通过Microarry筛选锁定Med1参与下所调控的关键因子及相关信号通路;再通过Binding assay、Gal4转录分析、CHIP等实验探究Med1作为治疗皮肤稳态失衡相关疾病潜在分子的可行性,从而为临床应用奠定理论基础。
期刊论文列表
专著列表
科研奖励列表
会议论文列表
专利列表
Vitamin D Receptor Is Required for Proliferation, Migration, and Differentiation of Epidermal Stem Cells and Progeny during Cutaneous Wound Repair.
皮肤伤口修复过程中表皮干细胞及其后代的增殖、迁移和分化需要维生素 D 受体。
DOI:10.1016/j.jid.2018.04.033
发表时间:2018-11
期刊:The Journal of investigative dermatology
影响因子:--
作者:Oda Y;Hu L;Nguyen T;Fong C;Zhang J;Guo P;Bikle DD
通讯作者:Bikle DD
Phospholipase Cepsilon deficiency delays the early stage of cutaneous wound healing and attenuates scar formation in mice.
磷脂酶 Cepsilon 缺乏会延迟小鼠皮肤伤口愈合的早期阶段并减弱疤痕形成。
DOI:--
发表时间:2017
期刊:Biochem Biophys Res Commun
影响因子:--
作者:Ren, Jiling;Man, Maoqiang;Liu, Peimei;Hu, Lizhi
通讯作者:Hu, Lizhi
The potential role of circRNA_004229 in hair/epidermal regulation after MED1 ablation in keratinocytes.
角质形成细胞MED1消融后circRNA_004229在头发/表皮调节中的潜在作用
DOI:10.1039/c9ra02322d
发表时间:2019-06-14
期刊:RSC advances
影响因子:3.9
作者:
通讯作者:
A topical heparinoid-containing product improves epidermal permeability barrier homeostasis in mice
含有类肝素的外用产品可改善小鼠表皮通透性屏障稳态
DOI:10.1111/exd.13985
发表时间:2019-08-01
期刊:EXPERIMENTAL DERMATOLOGY
影响因子:3.6
作者:Yao, Ye;Guo, Pan;Man, Mao-Qiang
通讯作者:Man, Mao-Qiang
Combined Deletion of the Vitamin D Receptor and Calcium-Sensing Receptor Delays Wound Re-epithelialization
维生素 D 受体和钙敏感受体的联合缺失会延迟伤口上皮再生
DOI:10.1210/en.2017-00061
发表时间:2017-06-01
期刊:ENDOCRINOLOGY
影响因子:4.8
作者:Oda, Yuko;Hu, Lizhi;Bikle, Daniel D.
通讯作者:Bikle, Daniel D.
Med1通过超级增强子时空特异性调控TGF-β信号通路对表皮稳态的影响及其机制研究
- 批准号:--
- 项目类别:面上项目
- 资助金额:52万元
- 批准年份:2022
- 负责人:胡立志
- 依托单位:
转录共激活因子MED1和SRC3差异化调控VDR信号通路在表皮自我更新及其稳态维持中作用机制的研究
- 批准号:81972962
- 项目类别:面上项目
- 资助金额:55.0万元
- 批准年份:2019
- 负责人:胡立志
- 依托单位:
磷脂酶Cε(PLCε)在皮肤真皮及表皮细胞中调控炎症细胞因子的机制研究
- 批准号:81301360
- 项目类别:青年科学基金项目
- 资助金额:23.0万元
- 批准年份:2013
- 负责人:胡立志
- 依托单位:
国内基金
海外基金
