GENE SILENCING IN THE RHESUS MACAQUE USING LENTIVIRAL VECTORS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 主要的生理功能，如新陈代谢、体温调节、睡眠和对压力的反应，都有昼夜节律。此外，这些节律的中断被认为是老年人睡眠-觉醒周期紊乱和季节性情感障碍（SAD）的病因。然而，负责协调人类节律功能的潜在神经内分泌机制知之甚少。最近，我的实验室发现，恒河猴的昼夜节律不仅受到位于大脑视交叉上核（SCN）的中央起搏器的控制，而且还受到肾上腺、肝脏和肾脏中的外周振荡器的控制。总之，这些新的发现意味着正常的生理功能是由几个不同的生物钟的协调行动来调节的，并且各种疾病状态可能源于它们之间的异常相位关系。为了开发针对人类昼夜节律相关疾病的有效疗法，我们需要更深入地了解灵长类动物昼夜节律产生的分子机制，以及更深入地了解外周振荡器如何同步其节律活动。这项初步研究的目的是开发一种有效的方法，选择性地沉默特定的生物钟。这个强大的工具将使我们能够系统地检查各种外围振荡器对正常生理的贡献，并为未来开发昼夜节律相关疾病的治疗方法奠定基础。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Major physiological functions, such as metabolism, thermoregulation, sleep, and response to stress, all have a circadian rhythm. Moreover, disruption of these rhythms is thought to contribute to the etiology of perturbed sleep-wake cycles in the elderly and to Seasonal Affective Disorder (SAD). However, the underlying neuroendocrine mechanisms responsible for coordinating rhythmic functions in humans are poorly understood. Recently, my laboratory discovered that circadian rhythms in the rhesus monkey are controlled not only by a central pacemaker, located in the suprachiasmatic nucleus (SCN) of the brain, but also by peripheral oscillators in the adrenal gland, liver and kidneys. Taken together, these novel findings imply that normal physiological functions are regulated by coordinated actions of several distinct biological clocks, and that various disease states may stem from abnormal phase relationships between them. To develop effective therapies for circadian-related disorders in humans, we need to have a deeper understanding of the molecular mechanisms responsible for circadian rhythm generation in primates, and a deeper understanding of how peripheral oscillators synchronize their rhythmic activity. The goal of this pilot study is to develop an effective way of selectively silencing specific body clocks. This powerful tool would enable us to systematically examine the contribution of the various peripheral oscillators to normal physiology and to lay the groundwork for future development of therapies for circadian-related disorders.