缩胆素1受体调节成体中脑神经发生的研究

Parkinson's Disease (PD) is the second commonest neurodegerative disease and there is no cure for it so far. Despite a number of adverse effects following long-term treatment, the mainstay of pharmocotherapy for PD remains L-DOPA and dopamine receptor agonists. Cell replacement employing exogenous or endogenous stem cells may become an important clinical therapy for PD in the next decade or two. Endogenous cell replacement, i.e., manipulation of adult neurogenesis may circumvent ethical issues, tumor formation and immune rejection, which are inherent in exogenous cell transplant. However, spontanous neurogenesis in the adult midbrain is very limited and not potent to halt the PD progression or improve motor symptoms. Therefore, stimulation of neurogenesis in the adult midbrain is the key issue for the therapy. Previously in our study, we revealed that the gene ablation of cholecystokinin 1 receptor (CCK 1R) selectively decreased the number of newborn dopaminergic neurons in the adult olfactory bulb. In this propasal, we hypothesize that CCK1Rs also regulate the neurogenesis in the adult midbrain and substantia nigra. Using distinct animal models , we will examine CCK 1R's regulation in midbrain neurogenesis under physiological and pathological conditions. We will also investigate the ontogenesis of newborn midbrain cells such as cellular compoments of subependymal zone lining aqueduct, migration path of newborn cells toward substantia nigra, migration and survival timecourse and expression of distinct receptors etc. With these knowledge, we will better understand the cellualr infrastructure of neurogenesis in the adult midbrain, and help to explore more pharmocotherapies targeting different genes, proteins, neurotransmitters, receptors as well as migratory and maturational stages of newborn neural cells.

帕金森病是一种无法治愈的神经退行性变疾病。目前的以左旋多巴为主的药物疗法在长期治疗后多出现疗效下降和其他诸多不良反应。与外源性干细胞移植治疗帕金森病不同，内源性细胞替代疗法不受伦理问题、肿瘤形成和免疫排斥等难题的困扰。寻找有效的调控途径来增强自体中脑的神经发生是这种疗法成败的关键。申请人在前期的研究中发现缩胆素1受体（CCK 1R）选择性地调节嗅球内多巴胺能神经元的成体发生。因此，我们假设相似的调节机制也存在于中脑和黑质。在本课题中，我们将利用多种动物模型从不同角度研究中脑的成体神经发生和有CCK 1R参与的调节机制。我们将观察中脑导水管室管膜下区的超微细胞结构，CCK 1R的分布，新生中脑神经细胞的起源部位，移行途径和成熟过程。同时我们还将计数在应用CCK 1R激动剂和拮抗剂条件下新生细胞的数量变化。我们的研究将帮助加深对成体中脑神经发生的认识，并有可能为治疗帕金森病开辟新的途径。

绝大部分的阿尔海默茨病（AD）患者均为老年起病。其中，以胶质细胞活化和炎症细胞因子及趋化因子分泌为代表的慢性神经炎症在AD患者疾病形成过程中扮演了重要角色。趋化因子CCL11在正常老化过程中参与了认知功能下降，但是它是否参与AD的发病过程还不为人知。在我们的研究中，我们显示了海马神经元常规表达了CCL11的受体CCR3。同时体外研究表明CCL11的添加导致激酶CDK5和GSK-3β的活化，进而导致多靶点的Tau蛋白过度磷酸化。CCL11还介导了体外海马神经元Aβ的产生和树突脊的减少。以上的所有反应均会被CCR3的特异性拮抗剂GW766994所拮抗。另外，在APP/PS1双转基因鼠和野生型的脑脊液标本中，我们也观察到与年龄相关的CCL11水平的增高。与野生型鼠相比，这种增高在APP/PS1双转基因鼠尤为明显。APP/PS1双转基因鼠中对CCR3的敲除可以显著减少CDK5和GSK3β的磷酸化，Tau蛋白过度磷酸化，Aβ沉积，胶质细胞活化，突触丢失，以及纠正小鼠的空间学习和记忆缺陷。综上所述，与年龄相关的CCL11增长可能是AD致病的危险因素之一，因此拮抗其相关受体CCR3可能带来治疗获益。