溶酶体水解酶 cathepsin D 对神经元形态发育的调控及机制研究

cathepsin D普遍存在于真核细胞溶酶体中，是维持组织稳态不可或缺的酸性蛋白水解酶。缺失cathepsin D可导致神经元发育障碍和进行性神经变性，但具体机制不明。此前研究表明，缺失蛋白酶活性的cathepsin D同样参与调节凋亡，细胞增殖和迁移等多种生理过程，提示cathepsin D具有更多生物学活性。本项目组前期研究表明，cathepsin D在中性pH环境中具有非经典的磷酸酶活性，参与调控微丝细胞骨架的动态重组。神经元形态发育依赖微丝骨架的正确组装，因此，我们怀疑cathepsin D可能通过磷酸酶活性参与调控神经元形态发生。本项目计划应用分子遗传学、细胞生物学及行为学技术，尝试阐明cathepsin D对神经元形态发育的调控机制。本项目的顺利实施将有助于揭示神经元形态发育机制，为相关疾病的研究和诊疗提供全新靶点。

Cathepsin D (cathD) is a lysosomal hydrolase that degrades substrates in acidic compartments in eukaryocyte. It is essential for maintaining tissue homeostasis via its degradative function, and its loss leads to ceroid accumulation in the mammalian nervous system which results in progressive neurodegeneration. However, the mechanism of the regulation is still unclear. Previous study indicates non-proteolytic roles of cathD in regulating various biological processes such as apoptosis, cell proliferation and migration, suggesting that cathD has more biological activity. Our previous studies have shown that cathD has the function of cofilin phosphatase and can reorganize F-actin. The development of neuronal morphology depends on the correct assembly of the microfilament skeleton. Therefore, we suspect that cathD may be involved in regulating neuronal morphogenesis through phosphatase activity. Along these lines, our project intends to use molecular genetics, immunofluorescence chemistry, live cell imaging, intracellular calcium imaging analysis and behavioral analysis and other experimental methods to prove that cathD is necessary for regulating the dendritic structure of the nervous system, and try to clarify the role of cathD in regulating neuronal morphological development and the regulation mechanism of its function during the development of the nervous system. This project will help to reveal the mechanism of neuron morphology development, and provide new treatment ideas and therapeutic targets for the research of related diseases caused by abnormal neuron morphology, such as epilepsy, neurodegenerative diseases and so on.