利用条件性基因敲除小鼠对TBCB在神经元微管生物合成中作用及机制的研究

Neuronal migration disorders, which cause of cerebral palsy and epilepsy in infants and young children, is a group of diseases. Mutation in TUBA1A that encode a-tubulin, has recently been implicated in neuronal migration disorders. The mutant protein has a defective interaction with the cytosolic chaperonin, CCT, and are failure to stably interact with TBCB. It indicates that TBCB is important in these diseases. So far the function of TBCB is unclear and the inconsistent results are presented by the different experiments in vitro. To reveal the function of TBCB, we established the Thy1-Cre, TBCBflox/flox and CAG-Cre, TBCBflox/flox mice for in vivo and in vitro experiments. This research is to study the role of TBCB in microtube de novo formation through the tubulin folding and heterodimer assembly pathway and in the dynamic instability of microtubule through banding with EB1 and EB3, and to study the effect caused by microrube disorders to the growth and survive of neuron.

神经元移行异常病变是婴幼儿脑瘫及癫痫的重要病因。研究发现，该疾病与α-tubulin基因突变所导致的与微管蛋白折叠辅助因子B（TBCB）和CCT (cytosolic-chaperonin)绑定能力的缺失有关。揭示TBCB的功能，对揭示上述疾病的病因及发病机制极其重要。目前关于TBCB的功能知之较少，而已有的研究，均基于离体实验，不同的条件得到不同的实验结果。故要揭示TBCB的功能，在体研究必不可少。为此，我们建立了Thy1-Cre, TBCBflox/flox 和CAG-Cre, TBCBflox/flox条件性基因敲除小鼠模型，分别用于在体功能及离体机制的研究。本研究拟从TBCB影响α-Tubulin折叠，以及与EB1、EB3绑定的机制入手，研究其对微管从头合成及阳性端动态调节的影响，以及对神经元生长生存的影响。本项目将为微管的研究，以及相关疾病病因及发病机制的研究提供可靠的实验依据。