miR-132, a new player in HIV/neuroAIDS

miR-132，艾滋病毒/神经艾滋病的新参与者

• 批准号: 8998527
• 负责人: Johnny J He
• 金额: $ 53.13万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8998527
• 关键词: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Address; Affect; Agreement; Astrocytes; Astrocytosis; Biochemical Genetics; Biological Markers; Brain; Brain Diseases; CCL2 gene; CD4 Positive T Lymphocytes; Calcium; Caring; Categories; Cells; Central Nervous System Infections; Cerebrospinal Fluid; Cessation of life; Chromatin Remodeling Factor; Cognitive; Cyclic AMP-Responsive DNA-Binding Protein; Development; Disease Progression; Endoplasmic Reticulum; Epigenetic Process; Fascicle; Functional disorder; Gene Expression; Gene Targeting; Genetic Transcription; Glial Fibrillary Acidic Protein; Goals; HIV; HIV Infections; HIV-1; Homeostasis; Human; Individual; Infection; Injection of therapeutic agent; Integration Host Factors; Interleukin-6; Knockout Mice; Knowledge; Laboratories; Life; Link; Lymphocyte; Mediating; Mediator of activation protein; Methyl-CpG-Binding Protein 2; Microglia; Minor; Molecular; Molecular Profiling; Monitor; Motor; Mus; Neuraxis; Neurites; Neurodegenerative Disorders; Neurologic; Neurologic Dysfunctions; Neurons; Pathogenesis; Pathology; Patients; Process; Property; Proteins; Recruitment Activity; Regulation; Resources; Role; Sampling; Signal Transduction; Social Impacts; Symptoms; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Viral; antiretroviral therapy; brain cell; brain tissue; chemokine; cohort; cytokine; economic impact; fetal; genetic approach; immune activation; macrophage; monocyte; motor disorder; neurite growth; neuroAIDS; neurobehavioral; neuroinflammation; neuron loss; neuronal survival; neuropathology; neurotoxic; neurotoxicity; novel; novel marker; novel therapeutics; prevent; protein expression; public health relevance; tat Protein; treatment response; uptake

 DESCRIPTION (provided by applicant): HIV-1 infection of the central nervous system (CNS) occurs in a majority of AIDS patients and causes a variety of neurologic dysfunction and neuropathologies generally termed neuroAIDS. Microglia/macrophages and astrocytes to a less extent are the main HIV-1 target cells in the CNS, whereas neurons are rarely infected by HIV-1 but mostly affected in HIV/neuroAIDS. Therefore, several indirect mechanisms have been proposed for HIV/neuroAIDS pathogenesis. Among them is HIV-1 Tat protein. We have shown that Tat expression in the absence of HIV-1 infection is sufficient to cause neurobehavioral abnormalities and pathologies similar to most of those noted in HIV/neuroAIDS. Moreover, we have shown that Tat activates glial fibrillary acidic protein expression in astrocytes and contributes astrocyte dysfunction and subsequent neuron death. In the preliminary studies, we have found that Tat expression in astrocytes induces miR-132 expression and secretion in the form of exosomes and alters neurite growth and neuron survival. Importantly, we have also obtained preliminary evidence to link the cerebrospinal fluid (CSF) miR-132 levels to HIV/neuroAIDS pathogenesis. As a logical extension of our studies, we propose to further dissect the miR-132 function in astrocyte-mediated Tat neurotoxicity and HIV/neuroAIDS pathogenesis. Besides, we will determine the feasibility of using the CSF miR-132 level as a novel HIV/neuroAIDS biomarker. Thus, the underlying hypothesis for the current proposal is that Tat adversely affects astrocyte and neuron function and neuronal survival through regulation of miR-132 and its target genes. In other words, miR-132 is not only a mediator but also an indicator of Tat neurotoxicity and HIV/neuroAIDS pathogenesis. To test this hypothesis, we propose to address the following interrelated specific aims: (1) To characterize the mechanisms of Tat-induced miR-132 expression in astrocytes; (2) To determine effects of Tat-induced miR-132 expression on astrocytes; (3) To elucidate the mechanisms of miR-132-mediated Tat neurotoxicity; and (4) To investigate the potential of using CSF miR-132 as an HIV/neuroAIDS biomarker. We will use a combined molecular, cellular, biochemical, and genetic approach including use of primary mouse astrocyte cultures and neuron cultures, Tat transgenic and miR-132 knockout mice, primary human fetal brain cultures, brain tissues and CSF samples of HIV-1 cohorts in our studies. The answers sought have fundamental significance for understanding of this critical and pervasive protein HIV-1 Tat, and its role in HIV/neuroAIDS pathogenesis. In addition, these answers shall also aid in identification of HIV/neuroAIDS biomarkers and development of anti-HIV/neuroAIDS therapeutic strategies. The enormous amount of information available on HIV-1 Tat, HIV infection of astrocytes, and roles of miR-132/target genes in neurodegenerative diseases, the results obtained from our preliminary studies, and the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) resources make accomplishment of these aims practical.

 描述（由适用提供）：中枢神经系统（CNS）的HIV-1感染发生在大多数艾滋病患者中，并引起多种神经功能障碍和神经病理学通常称为神经助理。小胶质细胞/巨噬细胞和星形胶质细胞在较小程度上是CNS中的主要HIV-1靶细胞，而神经元很少感染HIV-1，但主要在HIV/神经剂中受到影响。因此，已经提出了几种用于HIV/神经辅助发病机理的间接机制。其中包括HIV-1 TAT蛋白。我们已经表明，在没有HIV-1感染的情况下，TAT表达足以引起与HIV/神经助剂中大多数人相似的神经行为异常和病理。此外，我们已经表明TAT激活星形胶质细胞中的神经胶质原纤维酸性蛋白表达，并导致星形胶质细胞功能障碍和随后的神经元死亡。在初步研究中，我们发现星形胶质细胞中的TAT表达以外泌体的形式诱导miR-132表达和分泌，并改变神经元和神经元的存活。重要的是，我们还获得了初步证据，以将脑脊液（CSF）miR-132水平与HIV/神经辅助发病机理联系起来。作为我们研究的逻辑扩展，我们建议进一步剖析星形胶质细胞介导的TAT神经毒性和HIV/HIV/神经辅助发病机理中的miR-132功能。此外，我们将确定将CSF miR-132水平用作新型HIV/Neuroaids生物标志物的可行性。这就是当前建议的基本假设是，TAT通过调节miR-132及其靶基因而不利地影响星形胶质细胞和神经元功能和神经元存活。换句话说，miR-132不仅是介体，而且是TAT神经毒性和HIV/神经辅助发病机理的指标。为了检验这一假设，我们建议解决以下相互关联的特定目的：（1）表征星形胶质细胞中Tat诱导的miR-132表达的机制； （2）确定TAT诱导的miR-132表达对星形胶质细胞的影响； （3）阐明miR-132介导的TAT神经毒性的机制； （4）研究使用CSF miR-132作为HIV/神经辅助生物标志物的潜力。我们将使用分子，细胞，生化和遗传方法组合，包括使用原代小鼠星形胶质细胞培养物和神经元培养物，TAT转基因和miR-132敲除小鼠，原发性人类胎儿脑培养物，脑组织，脑组织和HIV-1同类群的CSF样品。答案遭受的痛苦对于理解这种关键和普遍蛋白质HIV-1 TAT及其在HIV/神经辅助发病机理中的作用具有基本意义。此外，这些答案还应有助于鉴定艾滋病毒/神经辅助生物标志物和抗HIV/神经辅助治疗策略的发展。有关HIV-1 TAT，星形胶质细胞的HIV感染以及miR-132/靶基因在神经退行性疾病中的作用，从我们的初步研究获得的结果以及CNS HIV HIV抗逆转录病毒治疗研究（CHARTOR）资源的大量信息以及对这些目标实践的成就。