Dysregulation of circadian rhythm by HIV protein Tat

描述(申请人提供)：昼夜节律是24小时周期的生理功能，包括睡眠-觉醒周期、体温、认知表现、神经内分泌和神经免疫相互作用。在病理条件下，这些身体节律通常会发生变化。健康人的循环淋巴细胞有很强的昼夜节律振荡，在夜间达到峰值，但在HIV感染的患者中这种昼夜节律减弱。事实上，睡眠模式和昼夜节律的紊乱是艾滋病毒感染早期最常见的障碍之一，在艾滋病发作之前就是如此。位于下丘脑视交叉上核(SCN)的生物钟调节所有器官系统的昼夜节律。当SCN被消融时，昼夜节律减弱。我们推测，HIV感染患者的睡眠模式和昼夜节律的改变可能是由于扰乱了这种中央昼夜起搏器而引起的。HIV-1感染与多种神经疾病有关。虽然HIV-1的神经发病机制很复杂，但病毒蛋白Tat似乎扮演着重要的角色。SCN位于第三脑室底部，周围环绕着下丘脑室周器官(CVO)。CVO是大脑中最具渗透性的结构之一。由于TAT可以从感染细胞分泌到循环中，而且TAT很容易通过血脑屏障，我们推测SCN可能是TAT最早的靶点之一。虽然HIV-1感染影响神经功能的确切机制尚不清楚，但Tat可能在HIV感染早期昼夜节律的改变中发挥关键作用。这项建议将利用体外SCN脑片和体内常规模型来研究TAT蛋白在扰乱昼夜节律中的作用，以研究TAT重置生物钟的机制。我们的初步数据表明，TAT通过谷氨酸受体介导的信号通路重置生物钟。由于病毒在细胞和分子水平上引起的昼夜节律改变知之甚少，这项研究将对病毒的神经发病机制产生新的理解，并从长远来看可能导致治疗艾滋病毒感染患者的昼夜节律紊乱的方法。

DESCRIPTION (provided by applicant): Circadian rhythms are physiological functions that manifest a 24-hour period, including sleep-wake cycle, body temperature, cognitive performances, neuroendocrine and neuroimmune interactions. Under pathological conditions, these bodily rhythms are often altered. Healthy individuals have a robust circadian oscillation of circulating lymphocytes with the peak at night, but this circadian rhythm is diminished in HIV-infected patients. In fact, disruption of sleep patterns and circadian rhythms are among the most common disorders in the early stages of HIV infection, tong before the onset of AIDS. A circadian clock located in the suprachiasmaticnucleus (SCN) of the hypothalamus regulates the circadian rhythms of all organ systems. When the SCN is ablated, the circadian rhythms are diminished. We hypothesize that the alteration of sleep patterns and circadian rhythms in HIV infected patients may be caused by disrupting this central circadian pacemaker. HIV-1 infection has been associated with a variety of neurological disorders. Although the neuropathogenesis of HIV-1 is complex, the viral protein Tat appears to play an important role. The SCN is located in the base on the third cerebral ventricle surrounded by the hypothalamic circumventricular organs (CVO). The CVOs are among the most permeable structures in the brain. Since Tat can be secreted to the circulation from infected cells and Tat can readily cross the blood brain barrier, we hypothesize that the SCN may be among the earliest target of Tat. Although the exact mechanism by which HIV-1 infection affects neuronal function remains unknown, Tat may play a pivotal role in the alteration of circadian rhythms in the early stages of HIV infection. This proposal will investigate the role of Tat protein in the disruption of circadian rhythm using in vitro SCN brain slice) and in vivo routine models to study the mechanisms of circadian clock resetting by Tat. Our preliminary data suggest that Tat reset the circadian clock via a glutamate receptor mediated signaling pathway. Since little is known about viral-induced alteration of circadian rhythms at a cellular and molecular level, this research will yield novel understanding of viral neuropathogenesis and in the long-term may lead to therapeutic approaches to circadian rhythm disorders experienced by HIV-infected patients.