T细胞亚群分化异常和T细胞受体（TCR）基因谱系限制性选用是哮喘发生的关键原因。我们前期研究发现转录因子BCL11B有诱导T细胞向Th方向分化的趋势且能限制性选用多个TCR Vβ亚家族；基因表达谱分析推测其可能通过负调控TGF-β/SMAD信号通路发挥作用；同时哮喘患者可检测到BCL11B表达降低而TGF-β1、IL-17A表达上升。本研究拟进一步利用基因转染和RNA干扰技术体外改变哮喘动物和患者Th细胞中BCL11B基因，1）明确对Th17分化的调控作用；2）分析TGF-β/SMAD通路关键分子TGF-β1、SMAD2、RORγt等的改变；3）采用ChIP实验确定BCL11B的靶基因；4）通过基因扫描技术证实BCL11B主要影响Th17细胞Vβ谱系哪些亚家族。本项目的实施将明确BCL11B调控Th17分化在哮喘中的作用及分子机制，并为治疗哮喘提供新靶点。

The imbalance of T cells differentiation and the restrictive expression of T cell receptor (TCR) subfamily repertoire are the key cause of asthma. Our preliminary data showed that the transcription factor BCL11B promoted Th cells differentiation and repressed the clonality of the TCR Vβ repertoire. Futhermore，global gene expression profiling analysis indicated that BCL11B might exert these effects via targeting TGF-β/SMAD signal pathway. In addition, we found that downregulation of BCL11B was associated with upregulation of TGF-β1 and IL-17A in asthma patients (p<0.01). Herein, we will further explore the molecular mechanism of BCL11B in regulating Th17 differentiation and TCR Vβ repertoire. After modulating BCL11B expression in Th17 cells of asthma animal models and patients using gene transfer and RNA interference techniques, we will 1) evaluate the variety of Th17 cells to confirm the biological effects of BCL11B in Th17 cell differentiation; 2) detect the changes of the key molecules in TGF-β/SMAD signal pathway such as TGF-β1, SMAD2 and RORγt by performing quantitative RT-PCR and Western Blotting; 3) identify the target genes of BCL11B by Chromatin Immunoprecipitation (ChIP）；4）define the changes of Th17 cells TCR Vβ repertoire using Genescan analysis. Upon completing this project, we expect that some of our findings can be confirm the effect and molecular mechanism of negative regulation of Th17 differentiation by BCL11B. In addition, BCL11B may provide a new treatment-design or molecular therapeutic target of asthma.