Pou4f1对小鼠视网膜神经节细胞发育、存活与损伤的作用研究

POU-homeodomain transcription factors play essential role in neuronal development and differenciation. Pou4f family members Pou4f1, Pou4f2 and Pou4f3 are vital for neuronal development and survival. Conventional knockout research showed the ablation of Pou4f2 and Pou4f3 resulted in the death of a large number of RGCs.Meanwhile Pou4f2 was significantly downregulated before the RGCs programmed cell death appears in mouse glaucoma models. Though Pou4f family has similar structure and functional characteristics, the role of Pou4f1 in RGCs still unknown due to the early death of Pou4f1 knockout mice. In order to investigate the role of Pou4f1 in RGCs development and survival,conditional and inducible knockout technology will be employed to establish adult Pou4f1 knockout mice models and controlled opitic nerve cursh will be performed to imitate optic nerve injury status. Using above models, we will be able to explore the role of Pou4f1 in RGCs development and survial and find out how the expression change of Pou4f1 affects the apoptosis of RGCs under optic nerve injury status, which will provide data for the research on the potential function of Pou4f1 in gene diagnosis and theropy in RGCs degeneration diseases.

POU同源异型结构域转录因子在神经细胞的发育和分化中发挥着重要作用，其中Pou4f家族成员Pou4f1、Pou4f2和Pou4f3作用于神经元的发育及存活过程。前期研究发现Pou4f2和Pou4f3的表达缺失将造成视网膜神经节细胞（RGCs）的大量死亡，并且在青光眼RGCs出现程序性死亡前Pou4f2表达明显下调。虽然Pou4f族成员具有相似的结构和功能特点，但Pou4f1对RGCs的作用研究却因为Pou4f1基因敲除小鼠早期死亡，无法获得成体基因敲除模型而尚未开展。本项目将应用条件性和诱导性基因敲除技术，建立新的成体小鼠Pou4f1基因敲除模型，同时结合可控性视神经损伤技术，研究Pou4f1基因对小鼠RGCs发育和存活的作用，以及模拟视神经损伤状态时Pou4f1基因的表达改变对RGCs凋亡的影响。为探索Pou4f1基因在RGCs变性性疾病基因诊断和治疗中的应用研究提供实验依据。