Function of ceruloplasmin in the nervous system development

铜蓝蛋白在神经系统发育中的作用

• 批准号: 105730-2011
• 负责人: Paquin, Joanne
• 金额: $ 2.19万
• 依托单位: Université du Québec à Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2011
• 资助国家: 加拿大
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=475366
• 关键词: Function; ceruloplasmin; nervous; system; development

Ceruloplasmin (CP) is a multifunctional copper protein having ferroxidase, oxidase and antioxidant activities. It is an essential regulator of iron metabolism. CP is secreted by the liver and is the main carrier of circulating copper. This protein is also synthesized in the brain, a discovery of vivid interest since some neurodegenerative diseases are associated with iron deposits. Our previous studies showed that CP protects neurons against oxidative stress in vitro. We recently observed that CP binds, in vitro, to newly differentiated neurons from P19 embryonic stem cells and induces their aggregation. The neuroaggregative action involves an extracellular serine protease activity and is accompanied by a specific cleavage of the reelin protein. Extracellular serine proteases and reelin have a prominent role in the layered arrangement of neurons in the developing brain. Therefore, our recent results suggest a role of CP in neuronal organization of the developing nervous system. Our long term goal is to demonstrate and understand the function of CP in the developing nervous system. The present objectives are : (1) establish the physiological relevance of CP in the nervous system development in vivo, and (2) determine the mechanisms of the neuronal actions of CP in the P19 cell line, an appropriate model of nascent neurons. We will compare the neuronal lamination and the reelin expression in the developing and adult brains of normal and CP-deficient mice. Pharmacological agents and antibodies will be used in the P19 cell model to identify the signaling pathways and the proteolytic activities implicated in neuroaggregation and reelin cleavage. We will also further characterize the binding of CP to neurons. Our studies will contribute to define the funtion of CP in the developing nervous system. They could help understanding the etiology of some neuronal organization disorders such as epilepsy, schizophrenia, autism and mood disorders.

铜蓝蛋白是一种多功能铜蛋白，具有铁氧化酶、氧化酶和抗氧化活性。它是铁代谢的重要调节剂。CP由肝脏分泌，是循环铜的主要载体。这种蛋白质也在大脑中合成，这是一个有趣的发现，因为一些神经退行性疾病与铁沉积有关。我们以前的研究表明CP在体外保护神经元免受氧化应激。我们最近观察到，CP结合，在体外，新分化的神经元从P19胚胎干细胞，并诱导其聚集。神经聚集作用涉及细胞外丝氨酸蛋白酶活性，并伴随着reelin蛋白的特异性切割。细胞外丝氨酸蛋白酶和reelin在发育中的大脑中神经元的分层排列中具有突出的作用。因此，我们最近的研究结果表明CP在发育中的神经系统的神经元组织中的作用。我们的长期目标是证明和理解CP在发育中的神经系统中的功能。目前的目标是：（1）建立CP在体内神经系统发育中的生理相关性，和（2）确定CP在P19细胞系（一种合适的新生神经元模型）中的神经元作用的机制。我们将比较正常和CP缺陷小鼠的发育和成年大脑中的神经元分层和reelin表达。将在P19细胞模型中使用药理学试剂和抗体来鉴定涉及神经聚集和reelin切割的信号传导途径和蛋白水解活性。我们还将进一步表征CP与神经元的结合。我们的研究将有助于明确CP在神经系统发育中的作用。这有助于理解癫痫、精神分裂症、自闭症和心境障碍等神经元组织障碍的病因。