Tia1(p.P362L)突变所致的肌萎缩侧索硬化症(ALS)是新发现的一类因神经元损伤而出现进行性肌萎缩等症状，最终造成死亡的渐进性疾病，尚无有效的治疗方案。目前发现的Tia1(p.P362L)突变所致的9例ALS患者均为女性，说明该位点存在性别差异性致病作用，但机制尚不清晰，且缺乏合适的动物模型。申请人前期成功利用单碱基编辑技术构建Tia1(p.P362L)ALS家兔模型，并初步确定该模型可精准模拟ALS的临床表征。进一步研究发现其雌性个体发病症状更为严重，与人类临床报道相一致。因此，本课题拟利用构建的ALS兔模型，通过对性染色体基因表达调控、RNA剪切及神经炎性等多方验证，明确Tia1(p.P362L)突变在ALS中潜在的性别差异机制，推进家兔作为实验动物在神经退行性疾病领域的应用，同时对ALS疾病研究奠定相关的理论基础，有助于设计出基于不同性别的最优诊疗策略。

Tia1 (p.P362L) is a newly discovered pathogenic mutation of Amyotrophic lateral sclerosis (ALS), which is a kind of fatal neurodegenerative disease characterized by neuron damage and progressive neurogenic muscular atrophy. Currently, ALS is incurable due to the lack of effective therapeutic strategy. At present, 9 cases of ALS caused by Tia1 (p.P362L) mutation are all female, indicating that there is a gender difference in the pathogenesis of this locus, but the mechanism is not clear and there is a lack of suitable animal models. In the preliminary researches, the applicant had successfully constructed rabbit model of Tia1 (p.P362L) ALS with the single base editing technique. The model rabbit exhibits typical ALS symptoms like movement disorder and amyotrophy, indicating that the model can accurately recapitulate the clinical features of ALS. Further investigation showed that females turned to have higher severity of symptoms, which is consistent with clinical report. Therefore, based on the current ALS rabbit model, our research team is expecting to focus on the effect of sexual factors in Tia1 p.P362L pathology；investigating from multiple aspects like the regulation of sex chromosome genes, RNA splicing mechanism and proinflammatory effects; identifying the potential molecular mechanism of sexual differences in Tia1 (p.P362L) ALS. The study is expected of promoting the application of rabbits as experimental animals in the field of animal models of neurodegenerative diseases, and provide theoretical foundation for the prevention, diagnosis and therapy of ALS, and therefore facilitate the design and optimization of sex-specific diagnostic and therapeutic strategies.