Interspecies differences in glial secretions contributing to neuronal survival and death

神经胶质分泌物的种间差异导致神经元存活和死亡

• 批准号: 356033-2008
• 负责人: Klegeris, Andis
• 金额: $ 2.02万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2012
• 资助国家: 加拿大
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=504105
• 关键词: Interspecies; differences; glial; secretions; contributing

The neurodegenerative disorders of humans (e.g. Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis) and animals (e.g. scrapie, bovine spongiform encephalopathy) are characterised by irreversible loss of neurons. The non-neuronal cells in the brain, including microglia and astrocytes, can affect neuronal survival significantly. They do so by secreting various mediators that either enhance neuronal survival (i.e. neurotrophic factors) or cause neuronal death (i.e. neurotoxins). Furthermore, when these cells become activated, the repertoire of neuroactive molecules that they secrete may depend not only on the type of stimulus they encounter but also on the species of origin of the cells. Thus far, no systematic study has explored this aspect of glia-neuron signaling. Furthermore, there are glial mediators that have not been described yet. The proposed research will address these issues by studying secretions of microglial cells and astrocytes from humans and several other mammals, including rats, mice, pigs and sheep. I will analyse neuroactive products that are released by these cells after their exposure to several stimulants that are relevant to both human and animal neurodegenerative pathology and inflammatory mechanisms. I will also investigate the secretory arsenal of several glia-like cell lines to assess their usefulness as models of primary glial cells and I will search for novel, yet unidentified, neuroactive products of glial cells by using an unbiased proteomics technique. The proposed research program will answer a fundamental biological question about whether there are essential differences between glial cells from different species in their secretory responses to specific stimuli. An important practical application, crucial to an effective drug discovery process and translational research for human and animal neurodegenerative diseases, will be identification of the most appropriate in vitro model systems and species suitable for such research. These model systems could be used by other researchers to develop drugs with beneficial action in various neurodegenerative disorders of humans and animals, which could have substantial economic as well as health benefits to Canada.

人（例如阿尔茨海默病、帕金森病、肌萎缩性侧索硬化）和动物（例如羊瘙痒病、牛海绵状脑病）的神经退行性疾病的特征在于神经元的不可逆损失。脑中的非神经元细胞，包括小胶质细胞和星形胶质细胞，可以显著影响神经元的存活。它们通过分泌各种介质来增强神经元存活（即神经营养因子）或引起神经元死亡（即神经毒素）。此外，当这些细胞被激活时，它们分泌的神经活性分子库可能不仅取决于它们遇到的刺激类型，而且还取决于细胞的起源种类。到目前为止，还没有系统的研究探讨这方面的神经胶质细胞信号。此外，还存在尚未描述的神经胶质介质。拟议的研究将通过研究人类和其他几种哺乳动物（包括大鼠、小鼠、猪和绵羊）的小胶质细胞和星形胶质细胞的分泌物来解决这些问题。我将分析这些细胞暴露于与人类和动物神经退行性病理学和炎症机制相关的几种刺激物后释放的神经活性产物。我还将调查几个神经胶质样细胞系的分泌军火库，以评估其作为模型的主要神经胶质细胞的有用性，我将寻找新的，但身份不明，神经活性产品的神经胶质细胞通过使用无偏见的蛋白质组学技术。拟议的研究计划将回答一个基本的生物学问题，即不同物种的神经胶质细胞对特定刺激的分泌反应是否存在本质差异。一个重要的实际应用，一个有效的药物发现过程和人类和动物的神经退行性疾病的转化研究至关重要，将是最合适的体外模型系统和物种的识别适合这样的研究。这些模型系统可以被其他研究人员用来开发对人类和动物的各种神经退行性疾病具有有益作用的药物，这可能对加拿大产生巨大的经济和健康效益。