EXCITATORY AA RECEPTORS' ROLE IN ALZHEIMER'S & OTHER NEURODEGENERATIVE DISORDERS

兴奋性 AA 受体在阿尔茨海默病中的作用

• 批准号: 3789833
• 负责人: J W KUSIAK
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3789833
• 关键词: Alzheimer's disease; NMDA receptors; aging; gene mutation; genetic promoter element; glutamate receptor; molecular cloning; molecular pathology; neural degeneration; receptor expression; tissue /cell culture

The receptors for certain amino acids have complex roles in the brain in learning, memory and even in inducing neuronal death. These receptors are being studied for their possible role in various age-associated diseases including Alzheimer's disease. The major emphasis of this project is the investigation of the role of excitatory amino acids (EAA) receptors in neurodegenerative disorders of aging. This year we discovered a splice variant form of the NMDA subtype of EAA receptor. This isoform contains a deletion of 35 amino acids in the carboxy tail of the molecule. The deleted amino acids were found to be encoded on a separate exon in the rat genome. The deletion form is predominantly expressed in the cerebellum and brain stem while the full length form is found in rostral regions of the brain. We have found that both undifferentiated and differentiated PC-12 cells express both flip and flop forms of the GLUR-2 submit of the AMPA receptor, and that some previously uncharacterized splicing of this gene may occur in cell culture. We have just initiated work to clone and characterize the promoter region of the NMDA receptor. This work is critical in determining how the expression of the NMDA receptor is regulated at the molecular level. Finally, neural cell culture is being explored to examine NMDA and AMPA receptor subunit changes under conditions mimicking neurotoxicity and neuroprotection.

某些氨基酸的受体在大脑中具有复杂的作用 学习，记忆，甚至诱发神经元死亡。 这些受体是 正在研究其在各种年龄相关疾病中的可能作用 包括阿尔茨海默氏病。 该项目的主要重点是 研究兴奋性氨基酸（EAA）受体在 衰老的神经退行性疾病。 今年我们发现了一个剪接 EAA受体的NMDA亚型的变体形式。 这同工型包含一个 在分子的羧基尾部缺失35个氨基酸。 这 发现已删除的氨基酸编码在大鼠的单独外显子上 基因组。 缺失形式主要在小脑中表达 脑干，而全长形式是在鼻子区域中发现的 脑。 我们发现未分化和分化的PC-12 细胞表达AMPA的GLUR-2提交的翻转和翻板形式 受体，以及该基因的一些先前未表征的剪接 可能发生在细胞培养中。 我们刚刚开始工作以克隆和 表征NMDA受体的启动子区域。 这项工作是 确定NMDA受体的表达方式至关重要 在分子水平上调节。 最后，神经细胞培养 探索以检查条件下的NMDA和AMPA受体亚基变化 模仿神经毒性和神经保护性。