ALR是人类1型糖尿病（T1D）模型NOD小鼠的近交系，拥有NOD 70%的基因组但从不罹患T1D，其DC呈免疫耐受表型以摄取抗原及激活T细胞活化能力低下为特征。基因组测序和比对分析发现ALR第8号染色体编码的Myo9b基因较NOD及B6小鼠缺失11个氨基酸。遗传研究揭示Myo9b多态性调控如IBD等自身免疫性疾病的易感性，并有研究显示Myo9b与T1D易感性相关。在发现DC缺失Myo9b不能激活T细胞诱发获得性免疫的基础上，申报者拟在T1D病人阐明Myo9b调控T1D易感性并测序鉴定其功能性突变体；在NOD小鼠验证Myo9b缺失或转基因表达ALR突变体可预防或延迟T1D的发生发展；解析Myo9b调控T1D发生发展的细胞及分子机制；探索以Myo9b为靶点预防和治疗T1D的可行性。上述研究不仅为阐明T1D发病机制提供新认识，而且为开发以遗传因子为基础的T1D防治策略提供实验依据。

ALR is a congenic strain for type 1 diabetes (T1D)-prone NOD mouse; they share 70% genome, but unlike NOD mice, ALR mice nevenr develop T1D. Dendritic cells (DC) originated from ALR mice show a tolergenic phenotype as manifested by the lower antigen uptake and allogenic stimulatory capability. Congenic mapping revealed that the unique ALR genome encodes protective loci on chromosome 8, which renders these mice highly resistant to the induction of β cell specific autoimmune response. Indeed, high throughput genomic sequencing and comparative analysis characterized an 11-AA (amino acid) deletion for the ALR Myo9b gene on chromosome 8 as compared with that of NOD and B6 genome. Importantly, polymorphisms derived from Myo9b have consistently been demonstrated to be associated with genetic susceptibility for autoimmune diseases such as inflammatory bowl disease (IBD) and Crohn’s disease. Particularly, there is evidence also suggesting that Myo9b confers genetic susceptibility for T1D, and DC deficienct in Myo9b manifest impaired capability for induction of adaptive immune response. We thus hypothesize based on these preliminary studies that Myo9b is a suscetible gene for T1D. To address this hypothesis, we will first conduct a case/control study in T1D patients to demonstrate that Myo9b is associated with T1D susceptibility. Targeted high throughput genomic sequencing will be next carried out in both T1D patients and controls to characterize functional Myo9b rare variants. Myo9b knockout model and DC specific ALR Myo9b transgenic model will be further employed in NOD mice to confirm that altered Myo9b function regulates the development of spontaneous T1D. The underlying mechanisms by which altered Myo9b function modulation of T1D susceptibility will be also investigated. Finally, we will explore the feasibility of Myo9b to be a target for T1D prevention and treatment. These studies will not only provide novel insight into the understanding of T1D pathogenesis, but also be important for developing genetic factor based effective strategies for T1D prevention and treatment.