The Role of Homer in Maintenance of Wakefulness

随着时间的推移，衰老过程涉及到许多生理功能的逐渐恶化。睡哪一觉 服务的恢复功能也会随着年龄的增长而中断。睡眠和醒来都是碎片， 白天困倦是老年人的常见问题。白天昏昏欲睡可能是一种 夜间睡眠质量差或保持清醒的能力受损的后果。碎片化 觉醒很大程度上是由于无法维持长时间的清醒。实现这一目标的机制 变化及其后果是未知的。我们已经发现发现的Hmer支架蛋白 在突触后密度调节维持状态的稳定性。缺乏显性阴性的小鼠 Hmer 1的缩写，Hmer 1a，在活动期无法保持清醒，就像 年纪大了。我们假设，尾迹的维持需要Hmer 1a，而这一点的下降或丢失 机制导致在衰老过程中观察到的行为状态不稳定。这项提议将寻求 确定Hmer 1a促进尾流维持的分子机制及其作用方式 这些随年龄变化，以了解尾迹碎片随年龄变化的分子基础。我们的建议 研究将通过定位在哪里确定Hmer 1a依赖的持续觉醒控制的细胞基础 在大脑中，Homeria是必需的(特定的Aim1)。利用代谢型谷氨酸受体(MGluR) 我们将探索一种新的信号通路来确定 保持清醒的家庭行动(具体目标2)。在具体目标3中，我们将检查 在大脑中Homeria随着年龄的增长而减少的地方，研究与年龄相关的分子变化 Hmer 1a-mGluR信号通路，并最终确定Hmer 1a表达下降是如何发生的 衰老与无法保持清醒状态相关。

The aging process involves progressive deterioration of many physiological functions over time. Sleep which serves a restorative function is also disrupted with aging. There is fragmentation of both sleep and wake and daytime sleepiness is a common problem in the elderly. Increased daytime sleepiness may be a consequence of poor nighttime sleep quality or an impaired ability to maintain wakefulness. Fragmentation of wake occurs largely as a result of an inability to sustain long bouts of wakefulness. The mechanisms for this change and its consequences are unknown. We have found that Homerl scaffolding proteins that are found in the post-synaptic density modulate the stability of sustaining state. Mice lacking the dominant negative short form of Homer1, Homer1a, are unable to maintain wakefulness during the active period much like the aged. We hypothesize that the maintenance of wake requires Homer1a and that declines in or loss of this mechanism leads to behavioral state instability that is observed during aging. This proposal will seek to determine the molecular mechanisms by which Homer1a contributes to the maintenance of wake and how these change with age to understand the molecular basis of wake fragmentation with age. Our proposed studies will determine the cellular basis of Homer1a-dependent control of sustained wake by mapping where in the brain Homeria is required (Specific Aim1). Using metabotropic glutamate receptor (mGluR) transgenic knockin mice we will explore a novel signaling pathway to determine the mechanism underlying Homeria action in the maintenance of wakefulness (Specific Aim 2). In Specific Aim 3 we will examine where in the brain Homeria is reduced with aging, investigate age-related molecular changes in the Homer1a-mGluR signaling pathway and finally determine how declining Homer1a expression that occurs with aging correlates with the inability to maintain wakefulness.