METABOTROPIC GLUTAMATE RECEPTORS IN NEURODEGENERATION

描述（来自申请人摘要）：人类神经退行性疾病 如阿尔茨海默氏病（AD）、帕金森氏病（PD）、亨廷顿舞蹈病 HD和肌萎缩侧索硬化症（ALS）的特征在于成人 发病，进行性神经功能障碍，缺乏有效的 治疗这些常见的疾病会造成严重的残疾， 随着人口老龄化，公共卫生的重要性预计将增加。一 现在已经为每种疾病的家族性形式分离出了100多个致病基因， 这四种毁灭性的神经系统疾病， 转基因小鼠模型。虽然这种动物现在已经存在， 突变基因是如何导致神经系统疾病的仍不清楚。除非 神经退行性疾病的病因机制是明确的， 确定合理的治疗干预将是不可能的。的 神经递质谷氨酸盐被认为是导致 神经退行性疾病的病因学。具体来说，一类谷氨酸盐 受体，代谢型谷氨酸受体（mGluRs），可以特异性地 在许多神经退行性疾病中是异常的。 本项目将在转基因小鼠中检测代谢型谷氨酸受体 使用配体结合，原位杂交， 免疫组织化学和Western印迹。mGluR表达的改变 水平也被预测对异常的突触有直接的影响。 这是神经退行性疾病的特征。因此我们 还将探索谷氨酸相关的细胞内信号通路， 转基因小鼠的大脑。最后，如果mGluR功能障碍是 针对mGluRs的药物可能会改善某些疾病的症状， 这些模型。我们将测试是否给予mGluR活性药物 改善这些疾病的小鼠模型的临床结果。

Description (From the applicant's abstract): Human neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS) are characterized by adult onset, progressive neurologic dysfunction, and a paucity of effective therapies. These common disorders produce substantial disability, and their importance to public health is expected to increase as the population ages. One or more causative genes have now been isolated for familial forms of each of these four devastating neurologic illnesses, making possible the development of transgenic mouse models. Although such animals now exist, the exact mechanisms by which mutant genes cause neurologic disease remains unclear. Unless the etiologic mechanisms underlying the neurodegenerative diseases are clearly identified, rational therapeutic interventions will be impossible. The neurotransmitter glutamate has been implicated as a causative factor in the etiology of neurodegenerative disorders. Specifically, one class of glutamate receptors, the metabotropic glutamate receptors (mGluRs), may be specifically abnormal in many of the neurodegenerative disorders. This project will examine metabotropic glutamate receptors in transgenic mouse models of AD, PD, HD, and ALS using ligand binding, in situ hybridization, immunohistochemistry, and Western blotting. Alteration of mGluR expression level is also predicted to have direct implications for the abnormal synaptic functioning which is characteristic of neurodegenerative diseases. Thus, we will also explore glutamate-related intracellular signaling pathways in the brains of transgenic mice. Finally, if mGluR dysfunction is an important part of disease etiology, drugs targeting mGluRs may ameliorate symptoms in certain of these models. We will test if administration of mGluR-active medications improves clinical outcome in mouse models of these diseases.