有氧运动通过ALDH2调节CaMKII羰基化改善帕金森病纹状体突触可塑性的效应与机制

基底核相关的运动障碍性疾病PD与纹状体突触的形态结构和生理机能紊乱密切相关。申请人前期研究运动适应性增龄性老化和6-OHDA致PD在体实验，采用改良亲和素-生物素磁珠富集羰基蛋白质组学等方法，发现CaMKIIα羰基化在PD突触可塑性中起着关键病理作用，运动可通过ALDH2降解CaMKIIα羰基化。本项目拟构建RNA干扰CaMKIIα和施加ALDH2抑制剂Daidzin的两个运动适应性PD模型，验证并解释运动抗逆锻炼机制。同时，拟构建中脑多巴胺能母细胞系SN4741的PD细胞模型，施加ALDH2激动剂Alda-1和过表达处理，探明激活ALDH2降解CaMKIIα羰基化并促其表达对PD纹状体突触可塑性的影响及机制。本项目探索PD发生过程中的CaMKIIα羰基化及运动适应性的调控机制，致力于筛选神经退行性病变早期的新靶标，为PD的发生发展和运动延缓神经退行及PD病变的机制提供理论与康复指导意义。

Basal ganglia related Neurodegenerative diseases of Parkinson's disease was closely related to the striatum neural pathways，and striatal morphological structure and physiological function obstacle. This project prophase studied and constructed two parts of model that are striatal aging model and 6-OHDA-induced Parkinson's disease model. The carbonyl proteins were enriched by the improved avidin-biological enrichment protein carbonyl proteomics and identified by ESI-Q-TOF-MS/MS mass spectrometry. It showed that CaMKII alpha protein carbonylation is a neurotoxin key physiological pathology molecules in Parkinson's disease. CaMKII alpha protein carbonylation can be degraded by promoting the expression of ALDH2 in regular aerobic exercise.This project intends to build CaMKII alpha RNA interference and build ALDH2 inhibitors (Daidzin) of two PD model, to explore CaMKII alpha and its modified in the neurotoxin pathways related protein carbonylation to provide more direct evidence that the effect of regular aerobic exercise in Parkinson's disease. At the same time, we plan to build SN4741 midbrain dopaminergic cell in mice model of PD cells, with exerting ALDH2 agonist Alda - 1 and handling the expression of ALD2, to explore CaMKII alpha protein carbonylation can be degraded and the expression CaMKII alpha can be promoted on synaptic plasticity, and to explain the adaptive mechanism on regular aerobic exercise that anti-aging and delay neurodegenerative diseases is a sterss resilience mechanism. This project intends to explore that Parkinson's disease was occurred in the process of carbonyl stress and related regulatory mechanism in the process of the movement, to screen that the early neural degeneration of new targets. It provides research information for sports science, exercise rehabilitation and geriatrics degenerative diseases including the early development process of Parkinson's disease in a very important theoretical and clinical rehabilitation significance.