Alteration of circadian rhythm and sleep by HIV protein Tat
HIV 蛋白 Tat 改变昼夜节律和睡眠
基本信息
- 批准号:7842990
- 负责人:
- 金额:$ 31.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-30 至 2013-08-31
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAction PotentialsAcuteAffectAnimal FeedAnimalsAstrocytesAttentionBlood - brain barrier anatomyBlood CirculationBody TemperatureBrainBreedingCD4 Lymphocyte CountCalciumCardiovascular systemCellsCircadian DysregulationCircadian RhythmsClinicalComplexCorpus striatum structureDataDietDiseaseDoseDoxycyclineElectroencephalographyEndocrineExhibitsExtracellular SpaceGlial Fibrillary Acidic ProteinGliosisGlutamate ReceptorGlutamatesHIVHIV Envelope Protein gp120HIV InfectionsHIV tat ProteinHIV-1Hippocampus (Brain)HormonesHourHumanHydrocortisoneHypothalamic structureIn VitroIndianaIndividualInfectionInterruptionLeadLightLong-Term EffectsLymphocyteLymphocyte CountMicrogliaModelingMolecularMotor ActivityMusN-Methyl-D-Aspartate ReceptorsNeuronsNeuropathogenesisNeurosecretory SystemsOrganPatientsPatternPerformancePhasePhysical activityPhysiologicalPlayProcessProductionPropertyRegulationResearchRetinalReverse Transcriptase Polymerase Chain ReactionRoleRouteSeriesSeveritiesSignal TransductionSleepSleep Wake CycleSliceStagingStructural ProteinStructureSystemTestingTetracyclinesTherapeuticThird ventricle structureTimeTransgenesTransgenic MiceUniversitiesViralViral ProteinsWild Type MouseWorkbasebody systemcircadian pacemakercytokineexperiencegp-120 Antigenimmune functionin vivolight entrainmentmonocytemouse modelnervous system disorderneurotransmissionneutralizing antibodynovelparticlepublic health relevancerelating to nervous systemrepairedsuprachiasmatic nucleustat Protein
项目摘要
DESCRIPTION (provided by applicant): Circadian rhythms are physiological functions that manifest a 24-hr period, including sleep-wake cycle, body temperature, neuroendocrine and neuroimmune interactions. 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. A circadian clock located in the suprachiasmaticnucleus (SCN) of the hypothalamus regulates the circadian rhythms of all organ systems. We hypothesize that the alteration of sleep patterns and circadian rhythms in HIV infected patients may be caused by disrupting this central circadian clock. 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 and sleep during HIV infection. Our previous study showed that acute application of Tat directly to the SCN both in vitro and in vivo could reset the circadian clock (Clark et al 2005). To assess the long term effect of Tat to the sleep and circadian timing system, we used the tetracycline-dependent and brain (GFAP) specific Tat transgenic mice. RT-PCR confirmed Tat expression in the SCN following doxycycline diet. The alteration of circadian rhythm and sleep pattern in the Tat-expressing mouse is comparable to clinical findings, characterized with reduced motor activity and impaired synchronization to the environmental light dark cycle. EEG analysis showed altered delta power in the Tat mice. The EEG data recorded from the Tat mice are similar to findings in AIDS patients (Darko et al 1995; Polich et al 2000). Since little is known about viral- induced alteration of circadian rhythm and sleep at a cellular and molecular level, this research may yield novel understanding of viral neuropathogenesis and potentially lead to therapeutic approaches to circadian rhythm disorders experienced by HIV-infected patients.
PUBLIC HEALTH RELEVANCE: Alteration of circadian rhythm and sleep occurs in AIDS patients with different disease stages and with a wide range of CD4 counts. Although the exact mechanism of HIV-1 neuropathogenesis remains poorly understood, viral proteins (gp41, gp120, and Tat) are thought to play a major role in the neural AIDS. Among these viral proteins, Tat is important because it can be secreted from infected cells to the extracellular space, subsequently affecting nearby neurons. Since our previous study demonstrated that Tat could reset the circadian clock in the brain, the suprachiasmatic nucleus (SCN), we hypothesize that the disruption of circadian rhythm and sleep during HIV infection could be a consequence of Tat on the SCN. To test our hypothesis, we used a transgenic mouse model that can selectively induce the expression of Tat in the brain when doxycycline is administered to the animals. RT-PCR confirmed Tat expression in the mouse SCN two weeks after feeding the animals with the doxycycline diet. Interestingly, the alteration of circadian rhythm in the Tat-expressing mouse is comparable to that found in the HIV-infected patients, characterized with reduced motor activity and impaired synchronization to the environmental light dark cycle. EEG analysis showed decreased delta power in the Tat transgenic mice compared to wild type mice.
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、神经内分泌和神经免疫相互作用。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。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。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中枢生物钟。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感染期间昼夜节律和睡眠的改变中起关键作用。我们之前的研究表明,在体外和体内将达特直接急性应用于SCN可以重置生物钟(Clark等人,2005)。为了评估达特对睡眠和昼夜节律计时系统的长期影响,我们使用四环素依赖性和脑(GFAP)特异性达特转基因小鼠。RT-PCR证实达特在多西环素饮食后SCN中表达。表达Tat的小鼠的昼夜节律和睡眠模式的改变与临床结果相当,其特征在于运动活动减少和与环境光暗周期的同步性受损。脑电图分析显示达特小鼠的δ功率发生了改变。从达特小鼠记录的EEG数据与AIDS患者的结果相似(Darko et al 1995; Polich et al 2000)。由于在细胞和分子水平上对病毒诱导的昼夜节律和睡眠改变知之甚少,因此这项研究可能会对病毒神经发病机制产生新的理解,并可能导致HIV感染患者经历的昼夜节律紊乱的治疗方法。
公共卫生关系:不同疾病阶段和CD 4计数范围广泛的艾滋病患者均存在昼夜节律和睡眠的改变。虽然HIV-1神经发病机制的确切机制仍然知之甚少,但病毒蛋白(gp 41、gp 120和达特)被认为在神经AIDS中起主要作用。在这些病毒蛋白中,达特是重要的,因为它可以从感染的细胞分泌到细胞外空间,随后影响附近的神经元。由于我们以前的研究表明,达特可以重置大脑中的昼夜节律钟,视交叉上核(SCN),我们假设,在HIV感染期间,昼夜节律和睡眠的中断可能是达特对SCN的结果。为了验证我们的假设,我们使用了一种转基因小鼠模型,当向动物施用强力霉素时,该模型可以选择性地诱导达特在脑中的表达。RT-PCR证实了用多西环素饮食喂养动物两周后小鼠SCN中的达特表达。有趣的是,Tat表达小鼠的昼夜节律的改变与HIV感染患者中发现的昼夜节律的改变相当,其特征在于运动活动减少和与环境光暗周期的同步性受损。EEG分析显示,与野生型小鼠相比,达特转基因小鼠的δ功率降低。
项目成果
期刊论文数量(0)
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{{ truncateString('JIAN M DING', 18)}}的其他基金
Alteration of circadian rhythm and sleep by HIV protein Tat
HIV 蛋白 Tat 改变昼夜节律和睡眠
- 批准号:
8312638 - 财政年份:2009
- 资助金额:
$ 31.21万 - 项目类别:
Alteration of circadian rhythm and sleep by HIV protein Tat
HIV 蛋白 Tat 改变昼夜节律和睡眠
- 批准号:
8136005 - 财政年份:2009
- 资助金额:
$ 31.21万 - 项目类别:
Dysregulation of circadian rhythm by HIV protein Tat
HIV 蛋白 Tat 导致昼夜节律失调
- 批准号:
6671828 - 财政年份:2003
- 资助金额:
$ 31.21万 - 项目类别:
Dysregulation of circadian rhythm by HIV protein Tat
HIV 蛋白 Tat 导致昼夜节律失调
- 批准号:
6806036 - 财政年份:2003
- 资助金额:
$ 31.21万 - 项目类别:
Dysregulation of circadian rhythm by HIV protein Tat
HIV 蛋白 Tat 导致昼夜节律失调
- 批准号:
7115688 - 财政年份:2003
- 资助金额:
$ 31.21万 - 项目类别:
Dysregulation of circadian rhythm by HIV protein Tat
HIV 蛋白 Tat 导致昼夜节律失调
- 批准号:
6945822 - 财政年份:2003
- 资助金额:
$ 31.21万 - 项目类别:
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