神经激肽和反应性星形胶质细胞间的相互作用及其在帕金森病治疗中的神经保护表现

Degenerative diseases are often regarded to a group of diseases that are incurable. One important neurodegenerative disease is Parkinson's disease and it is caused by degeneration of dopaminergic neurons in the brain. The disease is a serious motor disorder. Pharmacological intervention and neurosurgery are two available ways to combat the disease. However, both approaches cannot rescue and repair the damaged and dying dopaminergic neurons and the present treatments cannot really cure the disease. The present proposal will focus on the preventions of cell death, enhancement of neuronal survival against neurotoxicity, the repair of damaged dopaminergic neurons, and the roles of endogenous glial cells in rescuing neurons from cell death. Neurokinin (NK) is a group of neuropeptide and it is suggested to be involved in the control of autonomic, affective and higher cerebral functions. From previous reports, modulation of neurokinin peptide was observed in PD patients. Also, neurokinin peptide could modulate dopaminergic neurons survival in different experimental PD models by activating various intracellular signaling pathways. On the other hand, growing evidence has shown that astrocytes in great number play crucial roles in active regulation of neuronal micro-circumstance, synaptic functions and neural plasticity in the central nervous system. Based on our research background, we prepare to enhance our knowledge of the understanding of Parkinson's disease in the following ways: (1) the identification of neuroprotective effects of neurokinin agonist on the dopaminergic neurons; (2) the investigation on the cell repair of dopaminergic neurons with the endogenous release of neurotrophic factors in reactive astrocytes; (3) the linkage of neurokinin agonist and reactive astrocytes in the enhancement of neuroprotection. Our anticipation is that we can compare and generate important novel data from the present study and eventually we can provide more solid answers to one of the most intriguing questions in neuroscience, i.e., to find an ultimate cure for a currently incurable common neurological disease, namely Parkinson's disease.

帕金森氏病是由脑部多巴胺能神经元退化而引起的一种关键的神经退行性疾病。然而目前的药物以及神经外科医疗手段无法彻底治愈此病。本项工作将注重于如何避免细胞凋亡、增强细胞的存活力以抵抗神经毒性、修复受损的多巴胺能神经元，及利用内源性神经胶质细胞挽救濒死细胞等。神经激肽参与控制自主性、情感性及更高级的大脑功能，也可通过激活多种细胞信号传导通路来促进多巴胺能神经元的存活。过去的研究结果显示，帕金森病患者体内发生了神经激肽的表达调节。同时，大量星形胶质细胞的存在对于神经微环境、突触功能和神经适应性的积极调节有至关重要的作用。据我们的研究基础和成果，我们预备从下列几方面进行深入研究：鉴定神经激肽激动剂对多巴胺能神经元的保护作用；探究反应性星形胶质细胞释放的神经营养因子的细胞修复功能；检验神经激肽激动剂和反应性星形胶质细胞之间的相互作用是否能增强神经保护效果。预期此工作将为帕金森病的治愈之法找到新的方向。

本项目在前期工作基础上,围绕“神经激肽和反应性星形胶质细胞间的相互作用及其在帕金森病治疗中的神经保护表现”这一主题,开展实质性的科学研究工作。发挥两地的优势和有利条件,把神经分子生物学与神经科学有机地结合起来,联手进行帕金森治疗的深入研究。. 我们从下列几方面进行深入研究:鉴定神经激肽激动剂对多巴胺能神经元的保护作用;探究反应性星形胶质细胞释放的神经营养因子的细胞修复功能;检验神经激肽激动剂和 反应性星形胶质细胞之间的相互作用是否能增强神经保护效果。研究septide 通过NK1受体传导的神经保护作用，探究septide调节的细胞信号传导机制，特别是PI3K/AKT通路和MAPK/ERK通路。研究了反应性星形胶质细胞(BDNF亚型)的功能特质和表达时间窗。阐述在早期、中期和晚期帕金森病动物的脑基底核中,反应性星形胶质细胞和BDNF的表达模式。也研究了反应性星形胶质细胞(BDNF亚型)对多巴胺能神经元的神经保护作用。此外,星形胶质细胞对于神经元轴突伸长、多巴胺合成以及电生理特性的作用将被阐述。由此,在帕金森病始发时,BDNF所起的神经保护效果已经被证实。