Dysregulation of circadian rhythm by HIV protein Tat

描述（由申请人提供）：昼夜节律是表现为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，这些身体节奏往往被改变。健康个体的循环淋巴细胞有一个强大的昼夜节律振荡，在夜间达到峰值，但这种昼夜节律在HIV感染者中减弱。事实上，睡眠模式和昼夜节律的破坏是艾滋病毒感染早期最常见的疾病之一，早在艾滋病发病之前。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枢昼夜节律起搏器。HIV-1感染与多种神经系统疾病有关。虽然HIV-1的神经发病机制是复杂的，但病毒蛋白达特似乎起着重要作用。SCN位于第三脑室基底部，周围有下丘脑室周器（CVO）。CVO是大脑中最具渗透性的结构之一。由于达特可以从感染细胞分泌到循环中，并且达特可以容易地穿过血脑屏障，我们假设SCN可能是达特的最早靶点之一。虽然HIV-1感染影响神经元功能的确切机制尚不清楚，但达特可能在HIV感染早期昼夜节律的改变中起关键作用。本研究拟通过体外SCN脑片和体内常规模型研究达特蛋白在昼夜节律紊乱中的作用，探讨达特蛋白对生物钟的调控机制。我们的初步数据表明，达特重置生物钟通过谷氨酸受体介导的信号通路。由于对病毒引起的细胞和分子水平的昼夜节律改变知之甚少，这项研究将产生对病毒神经发病机制的新认识，从长远来看，可能会导致HIV感染患者经历的昼夜节律紊乱的治疗方法。

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.