线粒体自噬关键蛋白Parkin的动态修饰与化学小分子干预

Parkin调控线粒体自噬参与帕金森的发病，但其动态修饰影响功能的详细机制尚不清楚。本项目拟在前期研究的基础上，进一步考察在各种自噬诱导条件下Parkin的时空分布与动态修饰（丝氨酸磷酸化、酪氨酸磷酸化、泛素化）等属性；解析Parkin酪氨酸磷酸化位点及其对Parkin丝氨酸磷酸化和泛素化活性的影响，建立Parkin动态磷酸化-泛素化修饰与调控线粒体自噬功能之间的关联性；结合免疫电镜和超高分辨荧光成像等技术，通过改变去修饰酶SHP2的活性（过表达与敲减、激活与失活），来揭示Parkin的化学修饰规律与其功能的关系；借助化学生物学手段，筛选可靶向去修饰酶调控Parkin活性的化学小分子，以此为工具研究Parkin动态修饰的化学过程与调控机制，发现与确证调控线粒体自噬的新靶标和候选小分子。本项目对探索Parkin动态修饰影响线粒体功能以及寻找新的改善帕金森病的先导化合物均具有十分重要的意义。

Parkin is involved in the regulation of mitophagy in the pathogenesis of Parkinson's disease, however, the detailed mechanisms underlying its dynamic modification are still unknown. On the basis of previous studies, this project is 1) to investigate the temporal/spatial distribution and dynamic changes of Parkin in mitophagy; 2) to explore the regulatory mechanism underlying Parkin’s dynamic phosphorylation and regulation of mitophagy; 3) to reveal the effects of genetic modification (such as overexpression and knockdown of SHP2) on Parkin’s function using immuno-electron microscope and super-resolution imaging technology; 4) to screen chemical molecules targeting SHP2 to uncover the regulatory mechanism of Parkin in mitophagy using chemical biological methods. This project is of great significance for exploring the dynamic modification of Parkin in mitochondrial function and finding novel lead compounds that ameliorate mitophagy deficiency-triggered diseases.