IN VIVO ANALYSIS OF INTRACELLULAR SIGNALS CONTROLLING LYMPHOCYTE

细胞内信号在淋巴细胞发育中起着至关重要的作用 和功能。一组参与信号传递的分子已经 描述了这些分子之间的相互作用，并记录了它们之间的化学作用。 然而，激活是否以及如何激活在很大程度上仍然难以捉摸。 单个信号分子在体内对不同的 抗原受体基因调控等生理现象 重排、曲目选择、耐受性诱导、外围设备 淋巴细胞的激活和免疫记忆的维持。因为这些 只有在活体系统中才能恰当地解决问题，这 该项目专注于通过基因打靶和 转基因方法，并使用细胞、分子和生化 分析各种改变的信号分子对细胞周期的影响 体内淋巴细胞的发育、功能和病理。 我们目前有兴趣了解的监管职能 蛋白酪氨酸激酶CTK与RAS的适配分子Grb2 信号通路。出于这个原因，我们决定建立动物 这两个分子被灭活的模型 生殖系或处于动物发育的不同阶段。到目前为止，Ctkko 我们实验室已经获得了CtkFlowed嵌合小鼠。Es 还获得了携带Grb2ko和Grb2花突变的细胞系 并将用于产生携带相应突变的小鼠。 这些模型系统可能使我们能够详细研究细胞内 参与淋巴细胞发育和功能的信号机制 一种更具生理意义的情况。

Intracellular signalling plays a crucial role in lymphocyte development and function. A panel of molecules involved in signalling has been described and chemical interactions between these molecules documented. However, it remains largely elusive as to whether and how the activation of an individual signalling molecule contributes to various in vivo physiological phenomena such as control of antigen receptor gene rearrangement, repertoire selection, tolerance induction, peripheral lymphocyte activation and maintenance of immune memory. Since these questions can only be properly addressed in an in vivo system, this project focuses on developing animal models by gene targeting and transgenic approaches, and using cellular, molecular and biochemical methods to analyze the impact of various altered signalling molecules on the development, function and pathology of lymphocytes in vivo. We are currently interested in understanding the regulatory functions of the protein tyrosine kinase Ctk and the adaptor molecule Grb2 of the Ras signalling pathway. For this reason, we have decided to establish animal models in which these two molecules are inactivated either in the germline or at different stages of animal development. So far, the Ctkko and Ctkfloxed chimeric mice have been obtained in our laboratory. ES cell lines carrying Grb2ko and Grb2floxed mutations were also obtained and will be used to generate mice carrying the corresponding mutations. These model systems may allow us to study in detail intracellular signalling mechanisms involved in lymphocyte development and function in a more physiological situation.