Roles of Neurequlin-1 in Age Related Neuronal Changes

Neurequlin-1 在年龄相关神经元变化中的作用

• 批准号: 6950702
• 负责人: Jianxin Bao
• 金额: $ 31.37万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6950702
• 关键词: aging; behavior test; biological signal transduction; caloric dietary content; cochlea; dietary restriction; ear hair cell; ganglions; gene environment interaction; gene expression; genetic regulation; genetically modified animals; hearing; hearing disorders; hippocampus; histology; laboratory mouse; learning; molecular pathology; neural degeneration; neuregulins; neurogenetics; neurons; neuroregulation; nutrition related tag; protein structure function

DESCRIPTION (provided by applicant): Age related functional decline of nervous system is consistently observed, the sequence of causative molecular events for age related functional decline is unknown. This proposal focuses on possible roles of transmembrane Neuregulin-1 (Nrg-1) may have on this aging process. Our recent work revealed: (a) the cytoplasmic domain of Neuregulin-1 (Nrg-ICD) can translocate into the nucleus and regulate gene expression including that of PSD-95 and apoptotic genes; (b) Nrg-ICD regulates PSD-95 expression by binding to a transcription factor, Eos, and (c) during aging there is a correlation between nuclear translocation of Nrg-ICD and up-regulation of PSD-95 and BAK, a pro-apoptotic gene. The general hypothesis is that NRG-1 plays an essential role in age related neuronal changes. To test this hypothesis, we have made a conditional tissue-specific transgenic mouse model, which conditionally expresses Nrg-1 in several specific regions including hippocampus, spiral ganglion neurons, and outer-hair cells. By taking advantage of this mouse model, we will examine three related issues: (1) whether conditional overexpression of Nrg-1 in adult mice can alter age related hearing loss; (2) whether a conditional overexpression of Nrg-1 in adult mice can alter age related neuronal changes in hippocampus; (3) whether caloric restriction, the most effective way to delay the aging process, affects the role of Nrg-1 signaling pathways on age related neuronal changes. The ultimate goal of our research is to develop methods for prevention and treatment of age related functional decline of nervous system based on identifying molecular candidates involved in the aging process

描述（由申请人提供）：始终观察到与年龄相关的神经系统功能衰退，但与年龄相关的功能衰退的致病分子事件的序列尚不清楚。该提案重点关注跨膜 Neuregulin-1 (Nrg-1) 在这一衰老过程中可能发挥的作用。我们最近的工作揭示：(a) Neuregulin-1 (Nrg-ICD) 的胞质结构域可以易位到细胞核中并调节基因表达，包括 PSD-95 和凋亡基因的表达； (b) Nrg-ICD 通过与转录因子 Eos 结合来调节 PSD-95 表达，(c) 在衰老过程中，Nrg-ICD 的核转位与 PSD-95 和 BAK 的上调之间存在相关性。 -凋亡基因。一般假设是 NRG-1 在与年龄相关的神经元变化中发挥重要作用。为了验证这一假设，我们制作了一个条件性组织特异性转基因小鼠模型，该模型在多个特定区域（包括海马、螺旋神经节神经元和外毛细胞）条件性表达 Nrg-1。通过利用该小鼠模型，我们将研究三个相关问题：（1）成年小鼠中 Nrg-1 的条件性过度表达是否可以改变年龄相关的听力损失； (2) 成年小鼠中 Nrg-1 的条件性过度表达是否可以改变海马中与年龄相关的神经元变化； (3)热量限制作为延缓衰老过程的最有效方法，是否会影响Nrg-1信号通路对年龄相关神经元变化的作用。我们研究的最终目标是在识别与衰老过程相关的候选分子的基础上，开发预防和治疗与年龄相关的神经系统功能衰退的方法