Dysregulation of circadian rhythm by HIV protein Tat

HIV 蛋白 Tat 导致昼夜节律失调

• 批准号: 6671828
• 负责人: JIAN M DING
• 金额: $ 23.69万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6671828
• 关键词: HIV infections; circadian rhythms; electrophysiology; genetically modified animals; glutamate receptor; glutamates; host organism interaction; human immunodeficiency virus 1; laboratory mouse; suprachiasmatic nucleus; tumor necrosis factor alpha; virus protein

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.

描述（由申请人提供）：昼夜节律是24小时内的生理功能，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，这些身体节律经常被改变。健康个体的循环淋巴细胞具有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感染患者中减弱。事实上，睡眠模式和昼夜节律紊乱是艾滋病毒感染早期最常见的疾病之一，早在艾滋病发病前很久就出现了。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被切除时，昼夜节律减弱。我们假设HIV感染患者的睡眠模式和昼夜节律的改变可能是由于破坏了这个中央昼夜节律起搏器引起的。HIV-1感染与多种神经系统疾病有关。尽管HIV-1的神经发病机制很复杂，但病毒蛋白Tat似乎起着重要作用。SCN位于第三脑室底部，周围是下丘脑室周器官（CVO）。CVOs是大脑中最具渗透性的结构之一。由于Tat可以从受感染的细胞分泌到循环中，并且Tat可以很容易地穿过血脑屏障，我们假设SCN可能是Tat最早的靶点之一。尽管HIV-1感染影响神经元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。本研究将利用体外SCN脑切片和体内常规模型研究Tat蛋白在破坏昼夜节律中的作用，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。由于在细胞和分子水平上对病毒诱导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，并在长期内可能导致治疗hiv感染患者所经历的昼夜节律紊乱的方法。