KLF4调控的Notch信号通路改变对银屑病患者骨髓造血干细胞定向分化T细胞的影响

We had firstly found that much pathogenic activity of T cell differentiated from psoriatic hematopoietic stem cell is similar to the T cell separated from psoriatic peripheral blood. It was indicated that the abnormal T cell in psoriasis is closely related with dysfunction of hematopoietic stem cell definitive by hereditary factor. Recently, we found that Notch signal is abnormal in the differentiation process of hematopoietic stem cell to T cell in psoriasis. Study showed that KLF4 play a critical role in the process of hematopoietic stem cell differentiated to T cell, which also influence expression of Notch signal's target. With regards to these, the psoriatic hematopoietic stem cell will be investigated as follows: 1. the study on culture and differentiation of CD34+ cell; 2. the expression of KLF4 will be changed to be high-, none- and normal- expression, in order to identify the regulation of KLF4 to differentiation from CD34+ cell to T cell; 3. the Notch signal will be tested when KLF4 is diffenent expressing in differentiation; 4.the expression of KLF4 will be tested in DN2 to DN3 and DN3 stage for the purpose of KLF4 contribution to DN2 to DN3;5. the study of mature T cell.The topic is significant, substantial, and original.

前期我们在国际上首先发现银屑病造血干细胞定向分化的T细胞与银屑病外周血T细胞具有许多相似的特性，表明银屑病T细胞异常与遗传因素决定的造血干细胞异常密切相关。在此基础上新近我们又发现银屑病造血干细胞体外分化T细胞过程Notch信号有异常。研究表明KLF4是造血干细胞向T细胞分化的主控基因，显著影响着Notch靶基因的表达。为此我们拟在前期基础上对银屑病造血干细胞进行如下研究：①CD34+细胞培养及分化相关研究；②分化过程中干扰KLF4表达，使其呈高表达、不表达、自然表达状态，以明确KLF4在银屑病有何变化及是否是造血干细胞向T细胞分化的唯一调控者；③定向分化过程中观察KLF4不同状态下Notch信号通路；④DN2向DN3分化阶段及进入DN3阶段后观察两组KLF4关闭、再表达情况，以了解KLF4表达在DN2向DN3分化中的作用；⑤分化成熟T细胞相关研究。本课题是有重大意义的实质性原创项目。

银屑病是一种遗传与环境因素共同参与的慢性炎症性皮肤疾病，免疫异常在银屑病的发病中具有重要作用。我们的前期研究结果显示干细胞在银屑病的发病中扮演着重要的角色。.调整后项目对银屑病骨髓造血干细胞和骨髓间充质干细胞进行了研究。通过临床病例的研究，证实了造血干细胞移植可以传递银屑病，明显区别于外周血输注以后引起的短暂性银屑病皮损表现，为造血干细胞参与银屑病发病提供了临床依据。骨髓间充质干细胞的研究结果显示银屑病骨髓间充质干细胞在细胞增殖活性、自发凋亡率、免疫相关基因表达等方面均与对照存在差异，进一步明确了骨髓间充质干细胞在银屑病发病中的重要作用，为开展间充质干细胞移植治疗银屑病提供了理论依据。结合国内外银屑病干细胞的研究，我们综述了干细胞在银屑病发病中可能扮演的角色。项目对银屑病造血干细胞、骨髓间充质干细胞的研究均具有较高的创新性，且取得了很好的研究成果，从而确立了我国在干细胞银屑病发病机理研究领域的主导地位。