Neuronal Circuit Maintenance in Healthy Aging

项目摘要 这项研究的首要目标是确定随着年龄增长而保存神经元功能的新机制。 随着世界老龄化人口的稳步增加，神经退行性疾病的诊断数量 痴呆症预计在未来30年内增加一倍以上，这突显了我们迫切需要 了解大脑老化的细胞和分子基础。调节神经元的连接萎缩 交流会导致老化大脑中神经回路内的异常活动。活动如何变化 修改老化神经元的属性尚不清楚。大脑对神经元活动的适应部分是通过 诱导新的基因表达程序，编码电路可塑性的关键细胞类型特异性介体。 在老化的大脑中重新启动这些基因程序的调节器是否可以改善神经元的衰退 功能仍不清楚。 Bhlh-pas转录因子npas4是活性依赖基因的主要调节因子。 在老鼠和人类身上都有这种程序。NPAS4整合到NuA4/Tip60乙酰转移酶蛋白复合体中， 转录共激活因子和DNA修复复合体，它与学习和记忆有关 无脊椎动物。耐人寻味的是，NPAS4靶向的活性依赖元件会瞬间获得染色质 神经元激活时DNA损伤信号的标记(NPAS4 H_2AX)，增加了γ可能 在这些部位发挥作用，帮助修复由活动驱动的转录造成的损伤。在初步数据中，我 发现Npas4基因敲除的小鼠过早死亡，并有海马体细胞压力的迹象。本研究 我将检验这一假设，即新发现的NPAS4：NuA4复合体已经进化出保护作用 通过维持转录控制和基因组稳定来促进神经元的持续功能 活性依赖基因座。我将研究Npas4调节和活动随年龄的变化- 跨神经细胞类型的依赖基因诱导(目标1，K99)并确定其关键基因靶点 激活神经元中的复合体(Aim 2，K99)。在R00阶段，我将对这些想法进行扩展，以探索 这种活性依赖的蛋白复合体在修复针对增强子和 启动子，并将研究这种定向DNA修复活动如何随年龄变化(目标3，K99)。在漫长的岁月里 学期中，我将利用在K99期间获得的数据集以及生物信息学和神经生物学方面的新技能 训练期，以确定新的机制和分子，以保持细胞类型的特定功能 神经系统。我的最终目标是设计有针对性的策略来减缓或逆转神经元的衰退 最易患年龄相关性疾病的亚型。

Project Summary The overarching goal of this study is to identify new mechanisms that preserve neuronal function with age. As the world's aging population steadily increases, the number of diagnoses for neurodegenerative disease and dementia is projected to more than double within the next 30 years, underscoring our immediate need to understand the cellular and molecular basis of brain aging. Atrophy of the connections that mediate neuronal communication leads to aberrant activity within neural circuits in the aging brain. How changes in activity modify the properties of aging neurons is not yet clear. The brain adapts to neuronal activity in part via the induction of new gene expression programs encoding critical cell-type-specific mediators of circuit plasticity. Whether re-engaging the regulators of these gene programs in aging brains can ameliorate declining neuronal function remains unknown. The bHLH-PAS transcription factor NPAS4 constitutes a major regulator of activity-dependent gene programs in both mice and humans. NPAS4 integrates into the NuA4/TIP60 acetyltransferase protein complex, a transcriptional co-activator and DNA repair complex, which has been linked to learning and memory in invertebrates. Intriguingly, activity-dependent elements targeted by NPAS4 transiently acquire a chromatin mark of DNA damage signaling upon neuronal activation (γH2AX), raising the possibility that NPAS4 may function at these sites to help repair damage resulting from activity-driven transcription. In preliminary data, I discovered that Npas4 knockout mice die prematurely with signs of cell stress in the hippocampus. This study will examine the hypothesis that the newly identified NPAS4:NuA4 complex has evolved a protective role to promote the sustained functionality of neurons by maintaining transcriptional control and genome stability at activity-dependent gene loci. I will examine age-dependent changes to Npas4 regulation and activity- dependent gene induction across neuronal cell types (Aim 1, K99) and identify critical gene targets of this complex in activated neurons (Aim 2, K99). During the R00 phase, I will expand upon these ideas to explore a novel role for this activity-dependent protein complex in the repair of directed DNA damage at enhancers and promoters, and will examine how this directed DNA repair activity changes with age (Aim 3, K99). In the long term, I will leverage the datasets, and new skills in bioinformatics and neurobiology acquired during the K99 training period, to identify new mechanisms and molecules that preserve cell-type-specific function in the nervous system. My ultimate goal is to design targeted strategies to slow or reverse decline in the neuronal subtypes most susceptible to age-dependent diseases.