Tespa1在B细胞活化及相关自身免疫性疾病中的功能及机制研究

Tespa1是申请人博士期间课题组发现的一种新分子，仅在T细胞、肥大细胞和B细胞中特异性高表达。之前的工作中我们证实，Tespa1在胸腺T细胞发育和肥大细胞介导的过敏反应中起重要作用，但其在B细胞中的作用尚不明确。申请人在Tespa1-/-小鼠的预实验中发现，Tespa1的缺失引起小鼠外周B细胞功能异常，包括抗体产生显著增加，生发中心生成加速等，提示Tespa1在外周B细胞活化中发挥重要作用。本课题拟深入研究Tespa1对B细胞的作用及机制，工作思路为：①体外采用不同抗原刺激B细胞，探讨Tepsa1对B细胞增殖、凋亡、抗体产生等功能的影响，同时观察其对BCR下游信号通路的影响；②构建Tespa1在B细胞特异性缺陷的嵌合小鼠，在体内探讨Tespa1缺陷对小鼠B细胞发育及功能的影响；③在上述嵌合小鼠中建立类风湿性关节炎模型（CIA）,探讨Tespa1在B细胞相关的性自身免疫病中发挥的作用。

Tespa1 is a newly-discovered molecular expressed in T-cells, mast cells and B-cells. In our previous work, we proved that Tespa1 regulates the development of T-cells in thymus and the activation of mast-cells during anaphylaxis. However, the role of Tespa1 in B-cell remains unclear. Our preliminary data revealed elevated levels of immunoglobulins in the serum of Tespa1-deficient mice. We also found enhanced germinal center formation in Tespa1-/- spleen either before or after immunization. These observations suggested a possible role of Tespa1 in mediating BCR signaling and B-cells activation.This proposal is to further explore the role and underlying mechanism of Tespa1 in B-cell activation. We will continue our work to confirm the effect of Tespa1-deficiency on B cells inlcuding cell proliferation, apoptosis and antibody production. We will also study the role of Tespa1 on BCR downstream signaling transductions upon the activaiton of different antigens in vitro to reveal the molecular mechanisms of Tespa1 function in B cells. On the other hand, we will put our efforts in revealing the regulatory role of Tespa1 in vivo in the contexts of anti-infection humoral response and B-cell-relative autoimmune diseases such as Collagen-induced arthritis(CIA) by establishing these experimental models in the Tespa1-/-（μMT） chimeric mice.This study will provide us a novel insight into BCR signaling and maybe related to the further understanding of B-cells-related autoimmune disease.