Notch1的巴豆酰化修饰在糖尿病肾病进展中的作用机制研究

糖尿病肾病(DN)已成为威胁人类健康的严重疾病，亟需揭示其致病机制。新型赖氨酸巴豆酰化修饰（Lysine Cronalytion，Kcr）备受关注，且受去乙酰化酶Sirtuins等调控，而DN肾组织中Sirt1表达下降。课题组发现①调控血管新生的重要分子Notch1的Kcr水平在DN肾组织中升高；②减少内皮细胞Kcr水平，其血管新生能力减弱；③抑制血管新生或激活Sirt1将延缓DN进展。因此提出科学假设：高糖诱发Sirt1表达下降，导致Kcr-Notch1升高而过度激活Notch通路，引发异常血管新生，最终促进DN进展。为证实该猜测，课题组将采用可诱导、内皮细胞特异性敲除鼠及基因突变小鼠构建糖尿病模型，利用分子生物学、病理学、双光子成像等研究高糖环境中Notch1的Kcr修饰机制以及它调控血管新生在DN进展中的作用。

Diabetic nephropathy (DN) has become a serious disease that threatens human health, and its pathogenesis needs to be revealed. A novel lysine crotonylation (Kcr) modification has attracted much attention. The modification is regulated by the deacetylase Sirt1 and the like, while Sirt1 expression in DN kidney tissue is decreased. The research team found that ① Kcr levels of Notch1, an important molecule regulating angiogenesis, increased in DN kidney tissue; ② Decreased Kcr levels of endothelial cells weakened their angiogenesis ability; ③ Inhibition of angiogenesis or activation of Sirt1 would delay the progression of DN. Therefore, a scientific hypothesis is proposed: high glucose induces a decrease in Sirt1 expression, which leads to an increase in Kcr-Notch1 and excessive activation of the Notch pathway, triggers abnormal angiogenesis, and ultimately promotes DN progression. To confirm this conjecture, the research team will use inducible, endothelial cell-specific knockout mice and genetically mutant mice to build a diabetes model, and use molecular biology, pathology, two-photon imaging, etc. to study the Kcr modification mechanism of Notch1 in high glucose environments. And it regulates the role of angiogenesis in the progression of DN.