Huwe1调控proNGF对猴脑缺血后神经轴突可塑性作用的研究

The promotion of brain plasticity is an important way for functional recovery, and the axonal plasticity is the anatomic basis for the recovery of motor function. Growth associated protein GAP-43 is considered to be the marker protein of axonal regeneration, which recently found to be regulated by the growth factor family and its precursors, but its function is not clear. Our previous study found that the expression of proNGF is up regulated in monkey cerebral ischemia, and for the first time we found the expression of proNGF was strictly regulated by the ubiquitin ligase Huwe1, silencing Huwe1expression leads to up regulation of proNGF expression and down regulation of GAP-43, neurologic impairment is more serious, but this process can be blocked by proNGF inhibitor. Therefor we hapothesized that Huwe1 may plays a indirect role in axonal plasticity after stroke by regulating the expression of proNGF. In this research, we plan to further our study to determine the contribution of Huwe1 on the evolution of neuronal plasticity and axonal regeneration after focal cerebral infarction in nonhuman primates. Silencing Huwe1 expression will be conducted on models as a mean of intervention. Then we will use functional magnetic resonance imaging, electrophysiological and behavioral assessment to track the effect of Huwe1 and proNGF on the axonal plasticity. Our study may eventually provides the rationale for a new strategy to promote rehabilitation after stroke.

促进大脑神经可塑性是脑缺血后神经功能康复的重要途径，而轴突可塑性是运动功能恢复的解剖学基础。生长相关蛋白GAP-43被认为是轴突再生的标记蛋白，近来发现其受到神经生长因子家族及其前体的调控，但其作用尚不明确。我们前期研究发现猴脑缺血后上调神经生长因子前体proNGF的表达，且首次发现proNGF受到泛素连接酶Huwe1的严格调控，沉默Huwe1后使proNGF表达上调。预实验中发现proNGF抑制剂能够上调GAP-43表达。因此我们推测在脑缺血后Huwe1可能作用于proNGF间接调控神经轴突的可塑性。本课题拟在前期建立的恒河猴脑缺血模型基础上，以Huwe1调控proNGF介导GAP-43表达为主线，沉默Huwe1表达为干预手段，利用功能磁共振、行为学评估动态监测脑缺血后轴突重塑，探索Huwe1调控proNGF在脑缺血后神经重塑中的作用。本研究极可能为脑缺血后神经康复提供新的理论依据