神经限制性沉默因子REST在大脑衰老向退行性变转化中的作用机制研究

阿尔茨海默病（AD）是一种老年人最常见的神经系统退行性疾病，AD已成为严重危害我国老年人群健康的重大疾病之一，研究大脑衰老向退行性变的机制意义重大。在初步试验中我们使用AD模型小鼠的研究结果发现在正常衰老的小鼠大脑内神经元限制性沉默因子NRSF/REST表达上调，但是在AD模型小鼠脑内随着老龄化REST表达反而下调，由于REST与神经再生密切相关，因此我们假设REST引起的神经再生障碍引起了大脑衰老向退行变的转变，为了验证这一假设，我们将在不同年龄的正常小鼠大脑内敲低REST表达以及AD模型小鼠大脑内升高REST的表达，研究衰老过程中REST表达变化对大脑海马神经细胞再生以及神经退行性变的影响，通过对比不同年龄神经干细胞转录组水平的变化明确REST参与大脑衰老向退行性变转化的分子机制。此研究将进一步明确神经再生障碍在大脑衰老和退行变中的意义，并为积极发展AD的治疗提供新的理论基础。

Alzheimer’s disease is the most common form of neurodegeneration. How the brain changes from aging to neurodegeneration remains elusive. Our preliminary studies have shown that RE1 silencing transcription factor (REST) is elevated with aging in normal mice; however, both mRNA and protein levels of REST are reduced with aging in AD mice. REST is a critical transcriptional factor involved in neuronal development as well as neurogenesis in adults. Thus we hypothesized that dysregulations of REST in aging in AD induced impairments in neurogenesis, which contributed to the transition from normal aging to neurodegeneration. To address this, we would knockdown REST expression using a Tet-on3G AAV system in different ages of Nestin-EGFP reporter mice. Neurogenesis and neurobehavioral tests would be conducted to reflect the effect of REST downregulation in neurodegeneration. Concormitantly, REST expression in AD mice at different ages would be upregulated by a Tet-on3G AAV system. And neurogenesis, AD pathogenesis as well as memory tests would be conducted to reflect the results of REST upregulation in AD mice on neurodegeneration. The target genes of REST in neurogenesis would be determined by 2nd generation sequencing conducted using neural stem cells at different ages and different expression levels of REST. The target genes would be verified in neurogenesis in vitro and in vivo. The elucidation of REST and neurogenesis in mice at different ages will provide the new understandings of brain aging and neurodegeneration.