Roles of Neuregulin-1 in Age Related Neuronal Changes

Neuregulin-1 在年龄相关神经元变化中的作用

• 批准号: 6812950
• 负责人: Jianxin Bao
• 金额: $ 31.14万
• 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/6812950
• 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）：始终观察到神经系统的年龄相关功能下降，与年龄相关功能下降的病因分子事件的序列尚不清楚。该提案重点介绍了跨膜神经蛋白1（NRG-1）的可能作用，可能在这一衰老过程中具有。我们最近的工作表明：（a）神经蛋白-1（NRG-ICD）的细胞质结构域可以转移到细胞核中并调节基因表达，包括PSD-95和凋亡基因的基因表达； （b）NRG-ICD通过与转录因子，EOS和（c）结合在衰老过程中调节PSD-95的表达，NRG-ICD的核易位与PSD-95的核易位和pSD-95和Bak的上调之间存在相关性。一般假设是NRG-1在与年龄相关的神经元变化中起着至关重要的作用。为了检验这一假设，我们制作了有条件的组织特异性转基因小鼠模型，该模型在包括海马，螺旋神经神经元和外发细胞在内的几个特定区域有条件地表达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的条件过表达是否可以改变与年龄相关的听力损失； （2）成年小鼠中NRG-1的条件过表达是否可以改变海马相关的神经元变化； （3）热量限制是延迟老化过程的最有效方法，它会影响NRG-1信号通路对年龄相关的神经元变化的作用。我们研究的最终目标是开发基于识别涉及衰老过程的分子候选者的预防和治疗与年龄相关的神经系统功能下降的方法