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Mechanisms involved in HIV-1 Tat mediated neuronal damage

HIV-1 Tat 介导的神经元损伤的机制

基本信息

批准号：
8197513
负责人：
Francesca Peruzzi
金额：
$ 27.15万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197513
关键词：
Acquired Immunodeficiency Syndrome Affect Attention Binding Cause of Death Cell Nucleus Cell physiology Cells Clinical Complex Cytoskeleton Cytosol Data Encephalopathies Event Filament Genetic Translation HIV HIV-1 Highly Active Antiretroviral Therapy Immunosuppression Infection Integration Host Factors Knowledge Lead Life Mediating Messenger RNA MicroRNAs Microtubules Molecular Neuraxis Neuronal Dysfunction Neurons Nodule Organelles Patients Polyribosomes Process Protein Biosynthesis Proteins RNA RNA-Binding Proteins Research Personnel Sampling Signal Pathway Site Small RNA Synapses System Testing Therapeutic Intervention Translations Tubulin Ubiquitin Viral Regulatory Proteins base brain tissue factor C macromolecule mortality multicatalytic endopeptidase complex neurotoxicity novel prevent programs response tat Protein trafficking

项目摘要

Presently, more than 40 millions people are infected with HIV-1, and AIDS is the fourth leading cause of death worldwide. The introduction of highly active antiretroviral therapy (HAART) has greatly reduced HIVmediated immunosuppression and mortality. However, it may not prevent neuronal damage associated with HIV-1 infection, and progressive damage to the Central Nervous System may be an emerging problem as AIDS patients live longer. Among the factors that have been shown to promote neuronal toxicity, the viral regulatory protein Tat has captured special attention. Tat protein is secreted by HIV-1 infected host cells and has been shown to enter bystander non-infected cells, including neurons. Recently, we have identified a new mechanism by which Tat can induce neuronal damage. It involves the binding of Tat to tubulin, recruitment of the ubiquitin-proteasome system to the proximity of microtubules, and degradation of microtubuleassociated protein 2 (MAP2), a critical component of the cytoskeleton. Immunohistochemical analysis of clinical samples from HIV-1 encephalopathy (HIVE) brain tissues demonstrated a predominantly cytoplasmic presence of Tat in neurons near microglial nodules, and loss of MAP2 in 70% of the affected neuronal cells. The observation that Tat can deregulate cytoskeletal factors led us to hypothesize that molecular events that depend on cytoskeletal integrity such as RNA trafficking could be also impaired. Our preliminary data confirm the ability of Tat to alter the expression of a subset of small RNAs, called microRNAs, which are known translational repressers. On the basis of these results, we will test the hypothesis that in neurons Tat can alter protein synthesis by modulating the activity of the cytoskeleton, the proteasome and the expression of microRNAs translational repressers. We expect that results from this study will critically redefine our knowledge of Tat-mediated neurotoxicity, and can provide potential targets for more effective therapeutic intervention.

目前，有4000多万人感染了HIV-1，艾滋病是导致艾滋病的第四大原因世界范围内的死亡。高效抗逆转录病毒疗法(HAART)的引入大大减少了艾滋病毒介导的免疫抑制和死亡率。然而，它可能并不能防止与 HIV-1感染和中枢神经系统的进行性损害可能是一个新出现的问题，因为艾滋病患者寿命更长。在已被证明促进神经元毒性的因素中，病毒调节蛋白TAT引起了特别的关注。Tat蛋白由感染HIV-1的宿主细胞分泌，已经被证明可以进入旁观者未感染的细胞，包括神经元。最近，我们发现了一种新的 TAT诱导神经元损伤的机制。它涉及TAT与微管蛋白的结合，募集泛素-蛋白酶体系统靠近微管，与微管相关的降解蛋白质2(MAP2)，细胞骨架的重要组成部分。肿瘤的免疫组织化学分析来自HIV-1脑病(蜂窝)脑组织的临床样本显示，主要是细胞质在小胶质细胞结节附近的神经元中存在TAT，70%的受累神经细胞中MAP2缺失。 TAT可以解除对细胞骨架因素的调节，这一观察结果使我们假设分子事件依赖于细胞骨架的完整性，如RNA的贩运也可能受到损害。我们的初步数据证实 TAT改变已知的被称为microRNAs的小RNA子集的表达的能力翻译抑制者。在这些结果的基础上，我们将检验这样一个假设，即在神经元中，TAT可以通过调节细胞骨架的活性、蛋白酶体和蛋白的表达来改变蛋白质的合成 MicroRNAs翻译抑制因子。我们预计这项研究的结果将极大地重新定义我们的了解TAT介导的神经毒性，并可为更有效的治疗提供潜在靶点干预。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Induction of Id-1 by FGF-2 involves activity of EGR-1 and sensitizes neuroblastoma cells to cell death.

DOI：
10.1002/jcp.22505
发表时间：
2011-07
期刊：
JOURNAL OF CELLULAR PHYSIOLOGY
影响因子：
5.6
作者：
Passiatore, Giovanni;Gentilella, Antonio;Rom, Slava;Pacifici, Marco;Bergonzini, Valeria;Peruzzi, Francesca
通讯作者：
Peruzzi, Francesca

Cerebrospinal fluid MicroRNA profiling using quantitative real time PCR.