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的增长保持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 预计在未来30年内，痴呆症的发病率将增加一倍以上，这强调了我们迫切需要 了解大脑老化的细胞和分子基础。介导神经元的连接萎缩 交流会导致衰老大脑中神经回路的异常活动。活动的变化 改变老化神经元的特性尚不清楚。大脑适应神经元活动的一部分是通过 诱导编码回路可塑性的关键细胞类型特异性介质的新基因表达程序。 在衰老的大脑中重新参与这些基因程序的调节是否可以改善神经元的衰退， 功能仍然未知。 bHLH-PAS转录因子NPAS 4构成了活性依赖性基因的主要调节因子， 在老鼠和人类身上的程序。NPAS 4整合到NuA 4/TIP 60乙酰转移酶蛋白复合物中， 一种转录辅激活因子和DNA修复复合物，它与学习和记忆有关， 无脊椎动物有趣的是，NPAS 4靶向的活性依赖性元件瞬时获得染色质 神经元活化后DNA损伤信号的标志（γ H2 AX），提高了NPAS 4可能 在这些位点发挥作用，以帮助修复由活性驱动的转录引起的损伤。根据初步数据，我 发现Npas 4基因敲除小鼠过早死亡，海马体中有细胞应激的迹象。本研究 将检验新鉴定的NPAS 4：NuA 4复合物已经进化出保护作用的假设， 通过维持转录控制和基因组稳定性促进神经元的持续功能， 活性依赖性基因座。我将研究Npas 4调节和活性的年龄依赖性变化- 跨神经元细胞类型的依赖性基因诱导（Aim 1，K99），并确定其关键基因靶点 激活神经元的复合物（Aim 2，K99）。在R 00阶段，我将扩展这些想法， 这种活性依赖性蛋白复合物在修复增强子处的定向DNA损伤中的新作用， 启动子，并将检查这种定向DNA修复活性如何随年龄变化（Aim 3，K99）。从长远 在本学期，我将利用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 培训期间，以确定新的机制和分子，保持细胞类型特异性功能， 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， 最易受年龄依赖性疾病影响的亚型。

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.