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PGC-1alpha and Reelin: new players in HAND progression.

PGC-1alpha 和 Reelin：HAND 进程中的新玩家。

基本信息

批准号：
10172814
负责人：
BASSEL E SAWAYA
金额：
$ 39.63万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10172814
关键词：
AIDS/HIV problem Advocate Affect Antibodies Autopsy BDNF gene Binding Biogenesis Blood - brain barrier anatomy Brain-Derived Neurotrophic Factor Calcineurin Cell Line Cells Clinical Clinical Management Cognition Disorders Cognitive Communities Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic AMP-Responsive DNA-Binding Protein DNA Data Development Disease Down-Regulation Elements Genes Genetic Transcription HIV HIV-1 HIV-associated neurocognitive disorder Hippocampus (Brain)Human Impaired cognition In Vitro Infection Inflammatory Injections Intervention Laboratories Lead Learning Literature Measurement Mediating Memory Memory Loss Memory impairment Methylation Mitochondria Movement Mus Nerve Degeneration Neurocognitive Deficit Neurodegenerative Disorders Neurons Neuropsychology Pathway interactions Patients Persons Phosphorylation Plasmids Proteins Publishing Pyruvate Research Role Rolipram Testing Time Tissues Toxic effect Transgenic Mice Validation Viral Proteins Virus Virus Replication Work aged antiretroviral therapy brain tissue cell injury conditioned fear experimental study high throughput screening in vivo loss of function mouse model neuron loss novel novel therapeutic intervention object recognition prevent protein expression protein function tat Protein tissue/cell culture

项目摘要

SUMMARY It has been shown that patients carrying HIV-1 accumulate damage to cells and tissues that are not directly infected by the virus itself (e.g. neurons). Importantly, these include changes known as HIV- Associated Neurodegenerative Disorder (HAND) leading to the loss of neuronal functions. HAND is an outstanding problem in the clinical management of HIV-1 patients, because suppression of infectious virus by c-ART does not completely block neurodegenerative changes. Neuropsychological studies disclose cognitive alteration (such as loss of Spatial and Declarative Memory) in a substantial proportion of HIV-1 infected patients, and analysis of post-mortem brain tissues isolated from HIV-1 patients treated with c- ART show signs of neurodegeneration. In the absence of HIV-1 infection of neurons, a number of mechanisms have been proposed for HAND, including indirect inflammatory effects in the CNS and direct effects of viral proteins (e.g. Tat) shed from activated HIV-1-infected cells. The fact that these viral proteins enter the neurons through several pathways suggest the presence of many competing mechanisms that can contribute to HAND, each of which has its advocates. Their relative contributions to clinical disease in vivo remain to be sorted out, and this is an outstanding problem in HIV research. Studies from other neurodegenerative diseases described the cAMP responsive-element binding (CREB)-1 protein as a Key Regulator of the Memory. These studies also showed that loss of CREB protein expression and phosphorylation contributes to the development of neurocognitive impairments such as Spatial and Declarative Memory Alteration. Recently, we have obtained data showing a clear-cut effect of HIV-1 Tat on CREB protein phosphorylation and function in vitro (primary human and mouse neurons and in the neuronal cell line, SH-SY5Y) and in vivo (in mice injected with Tat then treated with Rolipram [activator of CREB]) (see BACKGROUND AND PRELIMINARY RESULTS). This finding is exciting for two reasons: (1) A correlation between CREB protein and neurodegeneration has been well-established in the literature, suggesting that this may be a significant contributory mechanism in HAND; and (2) Agents are available which can specifically restore CREB protein levels and function, offering an opportunity to test directly the contribution of this mechanism in vivo in mice. Our hypothesis is that Tat contributes to neurodegeneration via reduction of mitochondrial function, mediated by a decrease in CREB protein activity. We propose to test this hypothesis in tissue culture cells and in vivo in mice, and verify the intermediate role of CREB protein using the specific CREB activator: Rolipram. Therefore, in this revised application, we asked more specific and focus questions that will allow us to perform additional in vitro and in vivo studies to determine the exact mechanisms used by Tat leading to the loss of Memory by focusing mainly on the Tat-CREB function and to restore this lost declarative memory and learning. Completion of these studies will determine for the first time involvement of HIV-1 Tat in cognitive disorders such as, Learning Deficit and Spatial & Declarative Memory Impairment that is commonly observed in HIV- 1 patients as well as in aged persons. Using an Intervention (Rolipram) approach to prevent CREB loss of functions will help establishing a new therapeutic strategy (high throughput screening) to mitigate cognitive impairments associated with HIV-1 infection in HIV/AIDS patients. (Since the relation between Tat and BDNF was amply studied, we will propose BDNF experiments to validate our hypothesis only). !

摘要已有研究表明，携带HIV-1病毒的患者会对细胞和组织造成不直接的损害被病毒本身感染(例如神经元)。重要的是，这些变化包括被称为艾滋病毒相关的变化导致神经功能丧失的神经退行性疾病(手)。手是HIV-1患者临床管理中的一个突出问题，因为抑制 C-art感染病毒并不能完全阻止神经退行性改变。神经心理学研究披露相当大比例的认知改变(如空间和陈述性记忆的丧失) HIV-1感染患者的脑组织，并对经c-DNA处理的HIV-1患者死后脑组织进行分析。艺术显示出神经退化的迹象。在没有HIV-1感染神经元的情况下，已经提出了许多用于手的机制，包括中枢神经系统的间接炎症效应和病毒蛋白(如TAT)的直接效应激活感染HIV-1的细胞。这些病毒蛋白通过几种途径进入神经元的事实建议存在许多可以促进Hand的相互竞争的机制，每种机制都有自己的倡导者。它们在体内对临床疾病的相对贡献仍有待梳理，这是一个艾滋病研究中的突出问题。来自其他神经退行性疾病的研究描述了cAMP反应元件结合(CREB)-1 蛋白质是记忆的关键调节器。这些研究还表明，CREB蛋白表达的缺失而磷酸化有助于神经认知损伤的发展，如空间和陈述性记忆改变。最近，我们获得的数据显示，HIV-1TAT对CREB蛋白的磷酸化有明显的影响以及在体外(原代人类和小鼠神经元以及神经细胞系SH-SY5Y)和体内的功能 (在注射TAT的小鼠中，然后用罗利普兰[CREB激活剂]治疗)(见背景和初步结果)。这一发现令人兴奋，原因有两个： (1)CREB蛋白与神经退行性变之间的相关性已在文献中得到很好的证实。这表明这可能是一个重要的供款机制；以及 (2)可特异性恢复CREB蛋白水平和功能的药物，提供了一种有机会在小鼠体内直接测试这一机制的贡献。我们的假设是，TAT通过降低线粒体功能而导致神经退变，这是由CREB蛋白活性降低介导的。我们建议在组织培养细胞和小鼠体内验证这一假说，并验证中间产物使用CREB特异性激活剂罗利普兰研究CREB蛋白的作用。因此，在这个修订的应用程序中，我们提出了更具体、更有针对性的问题，使我们能够进行更多的体外和体内研究，以确定TAT导致主要集中在TAT-CREB功能并恢复这种丢失的陈述性记忆和学习。这些研究的完成将首次确定HIV-1与认知障碍的关系如，学习障碍和空间和陈述性记忆障碍，这是常见的艾滋病毒- 1例患者及老年人。使用干预(Rolipram)方法防止CREB损失功能将有助于建立新的治疗策略(高通量筛查)以缓解认知障碍艾滋病毒/艾滋病患者与艾滋病毒-1感染相关的损害。 (由于TAT和BDNF之间的关系已经得到了充分的研究，我们将提出BDNF实验来仅验证我们的假设)。好了！