METABOTROPIC GLUTAMATE RECEPTORS IN NEURODEGENERATION

描述(摘自申请者摘要)：人类神经退行性疾病 例如阿尔茨海默病(AD)、帕金森氏病(PD)、亨廷顿氏症 疾病(HD)和肌萎缩侧索硬化症(ALS)以成人为特征 起病，进行性神经功能障碍，缺乏有效的 治疗。这些常见的疾病会导致严重的残疾，他们的 随着人口老龄化，对公共卫生的重要性预计将增加。一 或更多的致病基因现在已经被分离出来，每一种家族性形式 这四种毁灭性的神经疾病，使发展成为可能 转基因小鼠模型。尽管这种动物现在存在，但确切的机制是 突变基因是如何导致神经系统疾病的，目前尚不清楚。除非 神经退行性疾病的病因学机制很清楚 明确、合理的治疗干预将是不可能的。这个 神经递质谷氨酸被认为是导致 神经退行性疾病的病因学。具体地说，有一类谷氨酸 受体，代谢性谷氨酸受体(MGluRs)，可能是特异性的 在许多神经退行性疾病中都有异常。 该项目将在转基因小鼠身上检测代谢性谷氨酸受体。 AD、PD、HD和ALS的配体结合、原位杂交、 免疫组织化学和Western blotting。MGluR基因表达的改变 水平也被预测对异常突触有直接的影响 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功能障碍是一个重要的部分 在病因学方面，靶向mGluRs的药物可以在某些情况下改善症状 这些模型中的。我们将测试mGluR活性药物的使用情况 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.