Roles of Neurequlin-1 in Age Related Neuronal Changes

描述（由申请人提供）：一直观察到与年龄相关的神经系统功能下降，与年龄相关的功能下降的致病分子事件的顺序是未知的。本研究的重点是跨膜神经调节蛋白-1 （Nrg-1）在这一衰老过程中可能发挥的作用。我们最近的研究发现：(a)神经调节蛋白1 （Neuregulin-1, Nrg-ICD）的胞质结构域可以转移到细胞核内，调控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的表达；(c)在衰老过程中，Nrg-ICD的核易位与PSD-95和BAK（促凋亡基因）的上调存在相关性。一般的假设是NRG-1在与年龄相关的神经元变化中起着重要作用。为了验证这一假设，我们制作了条件组织特异性转基因小鼠模型，该模型在海马、螺旋神经节神经元和外毛细胞等几个特定区域有条件地表达Nrg-1。利用该小鼠模型，我们将研究三个相关问题：(1)成年小鼠条件性过表达Nrg-1是否可以改变年龄相关性听力损失；(2)成年小鼠条件性过表达Nrg-1是否能改变海马中与年龄相关的神经元变化；(3)作为延缓衰老最有效的方式，热量限制是否会影响Nrg-1信号通路在年龄相关神经元变化中的作用。我们研究的最终目标是在确定参与衰老过程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

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