Wnt/β-catenin信号途径介导过表达BDNF刺激中脑神经发生的调控机制

Parkinson's disease (PD) is a serious neurological disease that the typical pathological characteristics are the selective degeneration and progressive development of the substantia nigra dopamine neurons. There is a lack of a permanent cure method for effective clinical effect. Aimed at the core of neurons degeneration mechanism, how to explore promoting endogenous neurogenesis, restore nerve loop imbalances, which has recently become the focus of cell therapy for Parkinson's disease. Our previous studies showed that glial cells' activation is an important source of brain derived-neurotrophic factor BDNF secretion, and Wnt/beta catenin signaling pathway participated in the regulation of brain activity occurred. Our preliminary experimental results also found that brain derived- neurotrophic factor BDNF involved in the process of the proliferation, migration and differentiation of midbrain neural stem cells or neural precursor cells, but the specific regulatory mechanism remains to be elucidated. Based on the previous studies, through the experimental methods ofPD model method, neural stem cells culture, Combined with methods of morphology and molecular biology, firstly we study that brain derived-neurotrophic factor BDNF over- expressed astrocytes stimulates the proliferation, migration, differentiation of midbrain nerve stem cells or neural precursor cells. Secondly we verify whether or not BDNF/Wnts co-express in dopamine neurons and regulate midbrain neurogenesis in vitro. At the same time, by Wnt receptor blockers or agonists, we further deliberate the co-existence model of BDNF/Wnts and the interaction relationship of BDNF/Wnts in animal model of Parkinson's disease. We hopely can clarify Wnts regulate the molecular mechanism of BDNF stimulating midbrain neurogenesis. It is anticipated that will provide scientific basis for the establishment of exploring a new PD neural protection treatment methods and a new strategy against PD.

帕金森病（PD）是以DA神经元选择性变性丢失为特征的严重神经疾病。目前尚无有效的治疗手段。针对神经元变性的核心机制，探索促进内源性神经发生、恢复神经环路失衡，成为PD治疗的研究热点。我们前期研究表明胶质细胞激活是BDNF分泌的重要来源，且Wnt/β-catenin参与调控中枢神经发生活动。预实验结果发现BDNF参与调节中脑NSCs增殖、迁移、分化的过程，但具体的调控机制有待阐明。本课题拟应用PD动物模型、神经细胞培养，结合形态学和分子生物学等方法,研究高表达BDNF刺激中脑神经发生的效应；探明 BDNF/Wnts分子在DA神经元的共表达及其参与PD中脑神经发生的调控；同时，应用Wnt受体阻断剂或激动剂，在PD动物模型验证BDNF/Wnts在体内的共存模式和两者相互作用关系。本课题为探明Wnts对BDNF刺激中脑神经发生的调控机制及探索建立PD神经保护治疗新方法，新策略提供科学依据。

帕金森病（PD）是以DA神经元选择性变性丢失为特征的严重神经疾病。尚无有效的治疗手段。针对神经元变性的核心机制，探索促进内源性神经发生、恢复神经环路失衡，成为PD细胞治疗的热点。本项目分别在细胞水平、动物水平及分子水平上，通过体外培养的神经细胞高表达BDNF的病毒转染实验，应用Transwell 细胞共培养体系，以及PD动物模型建立，结合形态学和分子生物学等多种实验手段：首先研究高表达BDNF刺激中脑神经发生的效应；探明BDNF/Wnts分子在DA神经元的共表达及其参与PD中脑神经发生的调控；同时，应用Wnt受体阻断剂，在PD动物模型进一步验证BDNF/Wnts在体内的共存模式和两者相互作用关系。结果表明： BDNF高表达对DA神经元具有神经保护作用，在中脑神经发生中，BDNF与Wnts分子共表达，具有正反馈调节作用。其机制可能涉及经典wnt/bata-catenin途径在体内与多系统发生交互作用有关。促进内源性神经营养因子的含量增加，能够补充PD患者变性丢失减少的DA神经元，部分地恢复和改善失衡的神经环路。本项目预期能够阐明Wnts对BDNF刺激中脑神经发生的调控机制，有望为探索建立PD神经保护治疗新方法，新策略提供科学依据。