P物质调控表皮干细胞β-catenin表达的机制及其在ESC分化中的作用研究

发布时间：2018-03-24 08:18

本文选题：表皮干细胞　切入点：P物质　出处：《第三军医大学》2006年博士论文

【摘要】：表皮干细胞(Epidermal Stem Cells，ESC)是皮肤发育、代谢以及损伤修复的重要细胞源泉，它不仅决定了表皮的形成和代谢，同时参与了毛囊的形态发生、生理周期的维持，以及损伤毛囊的修复。探讨ESC分化机制有助于寻找提高皮肤愈合速度与质量的措施，促进创伤愈合、提高创伤愈合质量。以往研究证实，ESC中的β-catenin是启动ESC分化进程与分化方向的关键蛋白。β-catenin是Wnt信号通路一种重要的胞内糖蛋白，低水平β-catenin是ESC保持干细胞状态的必要条件之一，当其表达上调后，ESC进入分化进程，β-catenin高水平表达的ESC向毛囊方向分化，若去除β-catenin则向表皮细胞方向分化。了解调控β-catenin表达的机制对探讨主导ESC的分化方向，促进毛囊的修复与重建的措施，以及开展皮肤组织工程中的毛囊重建均有重要意义。感觉神经肽P物质(substance p，SP)作为一种研究多年的细胞因子，以往对于它的研究主要集中于作为神经递质、激素和调质发挥的作用。创伤时不仅感觉神经末梢释放SP，同时在组织修复过程中，成纤维细胞、内皮细胞等修复细胞在神经末梢释放的SP的诱导下，上调SP基因及蛋白的表达，作为自分泌信号促进成纤维细胞、内皮细胞的增殖，并诱导多种参与愈合的其他细胞因子及蛋白(EGF、bFGF、β-catenin、VEGF、MMPs、NF-κB和fibronectin等)表达上调。尤其值得注意的是，本课题组前期研究发现，SP是诱导ESC分化和迁移的重要细胞因子。临床研究也注意到，，SP与ESC参与构建的毛囊的形态发育关系密切。皮肤注射SP可以诱导萎缩的毛囊再生；耗竭成鼠SP，毛囊会萎缩并消失。基于SP和β-catenin在ESC分化方向调控中的作用，提示SP可能通过调控β-catenin表达实现细胞外信号到细胞内信号的转导，进而调控ESC分化方向。CK1ε是β-catenin上游调控蛋白，与Wnt信号通路的GSK3协同控制β-catenin的Sr45的磷酸化，从而调控β-catenin表达：SP与特异性受体NK-R结合，水解4，5-二磷酸磷脂酰肌醇(PIP_2)生成1，4，5-三磷酸肌醇(IP_3)和二酰基甘油(DG)双信使，而PIP_2对CK1ε表达具有负向调节作用。基于以上依据，我们推论：1．SP通过调节β-catenin表达实现对ESC分化的调控；2)．
[Abstract]:Epidermal Stem cells ESCs are important cell sources for skin development, metabolism and damage repair. They not only determine the formation and metabolism of epidermis, but also participate in the morphogenesis of hair follicles and the maintenance of physiological cycle. To explore the mechanism of ESC differentiation is helpful to find ways to improve the speed and quality of skin healing, promote wound healing and improve the quality of wound healing. Previous studies have confirmed that 尾 -catenin is the key protein to initiate the differentiation and differentiation of ESC. 尾 -catenin is an important intracellular glycoprotein in Wnt signaling pathway, and 尾 -catenin is one of the necessary conditions for ESC to maintain stem cell status. When the expression of 尾 -catenin entered the differentiation process, the ESC expressed in high level of 尾 -catenin differentiated to the hair follicle, and if the 尾 -catenin was removed, it differentiated to the epidermal cells. Understanding the mechanism of regulating the expression of 尾 -catenin was helpful to explore the differentiation direction of the dominant ESC. It is of great significance to promote the restoration and reconstruction of hair follicles and to carry out the reconstruction of hair follicles in skin tissue engineering. Sensory neuropeptide substance substance (SP) is a cytokine that has been studied for many years. In the past, it was mainly studied as a neurotransmitter. During the process of tissue repair, the expression of SP gene and protein was up-regulated by fibroblasts, endothelial cells and other repair cells induced by SP released from nerve endings. As an autocrine signal, endothelial cells proliferate and induce the up-regulation of the expression of many other cytokines and proteins involved in healing, such as EGF- 魏 B and fibronectin. It is particularly noteworthy that, Our previous study found that SP is an important cytokine to induce differentiation and migration of ESC. Clinical studies also noted that SP is closely related to the morphological development of hair follicles constructed by ESC. Skin injection of SP can induce hair follicle regeneration in atrophy. According to the role of SP and 尾 -catenin in the regulation of differentiation direction of ESC, SP may realize the transduction of extracellular signal to intracellular signal by regulating the expression of 尾 -catenin. Furthermore, CK1 蔚 regulates the differentiation direction of ESC. CK1 蔚 is a 尾 -catenin upstream regulatory protein, which co-controls the phosphorylation of 尾 -catenin Sr45 with the GSK3 of Wnt signaling pathway, and thus regulates the expression of 尾 -catenin to bind to the specific receptor NK-R. Hydrolyzed PIP _ 2) to produce a double messenger of 1 / 4 / 5-inositol triphosphate (IP3) and diacylglycerol (DG), while PIP_2 has a negative effect on the expression of CK1 蔚. Based on the above, we infer that 1.SP regulates the differentiation of ESC by regulating 尾 -catenin expression.
【学位授予单位】：第三军医大学
【学位级别】：博士
【学位授予年份】：2006
【分类号】：R329

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