Interspecies differences in glial secretions contributing to neuronal survival and death

人类的神经退行性疾病（如阿尔茨海默病、帕金森病、肌萎缩侧索硬化症）和动物的神经退行性疾病（如痒病、牛海绵状脑病）的特征是神经元的不可逆丧失。大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的存活（即神经营养因子）或导致神经元死亡（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可能不仅取决于它们遇到的刺激类型，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索神经胶质-神经元信号传导的这一方面。此外，还有一些神经胶质介质尚未被描述。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。我将分析这些细胞在暴露于与人类和动物神经退行性病理和炎症机制相关的几种刺激物后释放的神经活性产物。我还将研究几种胶质样细胞系的分泌库，以评估它们作为原代胶质细胞模型的实用性，并将使用无偏倚的蛋白质组学技术寻找新的、尚未确定的神经活性胶质细胞产物。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，对于有效的药物发现过程和人类和动物神经退行性疾病的转化研究至关重要，将是确定最合适的体外模型系统和适合此类研究的物种。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有有益作用的药物，这可能对加拿大有巨大的经济和健康效益。

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.