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Molecular basis of neuronal dysfunction in AIDS

艾滋病神经元功能障碍的分子基础

基本信息

批准号：
7367117
负责人：
Francesca Peruzzi
金额：
$ 24.97万
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：
2004
资助国家：
美国
起止时间：
2004-03-02 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7367117
关键词：
AIDS Dementia Complex Acquired Immunodeficiency Syndrome Affect Animals Apoptosis Astrocytes Attention BHLH Protein Binding Binding Sites Biological Biopsy Brain CCAAT-Enhancer-Binding Proteins CDKN1A gene Cell Cycle Cell Cycle Checkpoint Cell Cycle Inhibition Cell Cycle Regulation Cell Survival Cell model Cells Clinical Cultured Cells Cyclins DNA-Binding Proteins Data Dementia Development Differentiation Inhibitor Doctor of Philosophy Enzymes Equilibrium Event Exhibits Family Family member Genes Genetic Transcription HIV-1 Helix-Turn-Helix Motifs Histologic Immunomodulators In Vitro Infection Laboratories Lead Light Maintenance Mediating Microglia Modeling Molecular Nerve Growth Factors Neuraxis Neuronal Differentiation Neuronal Dysfunction Neuronal Injury Neurons Nucleic Acid Regulatory Sequences Numbers Outcome Study Pathway interactions Patients Phosphotransferases Play Positioning Attribute Process Proliferating Proteins RNA Polymerase II RNA Sequences Range Rattus Recruitment Activity Regulatory Pathway Role SP1 gene Series Signal Pathway Site Staging Stimulus Tail Tars Testing Transcript Transcription Initiation Site Transcriptional Activation Up-Regulation Viral Genome Viral Regulatory Proteins Virus Virus Diseases base brain tissue cell injury cell type chemokine cyclin T1 cytokine extracellular genetic regulatory protein improved in vivo inhibitor/antagonist macrophage nervous system disorder neurogenesis neuron loss neuronal survival neurotoxic novel oncoprotein p21 promoter stem tat Genes tat Protein tool transcription factor uptake

项目摘要

DESCRIPTION (provided by applicant): HIV-1 invasion of the Central Nervous System, CNS, induces a variety of clinical abnormalities including dementia, also known as HIV-1 associated dementia, HAD. Histologically, brain biopsy from AIDS patients with neurological disorders exhibit a broad ranges of abnormalities, most notably neuronal cell loss. The absence of neuronal infection suggested an indirect role for the virus to induce neuronal cell damages. Results from a large number of studies indicated that expression and secretion of several cellular proteins including cytokines and immunomodulators from the infected macrophages, microglia, and astrocytes in the brain participate in the neuronal cell damages. In addition to cellular factors, the viral regulatory protein Tat has received attention due to its unique ability to be secreted by the infected cells, enter into uninfected cells and alter the expression of cellular genes in the absence of viral infection. Moreover, Tat protein has been shown to have neurotoxic activity, most likely through dysregulating signaling pathways that are critical for neuronal cell survival. By using PC12 neuronal cell model, as well as primary rat neuronal cells, we demonstrated that Tat stimulate the expression of Id gene, a known cellular protein that inhibits differentiation of neuronal cells. Id, by affecting expression and activity of several factors which control the cell cycle promotes unscheduled entering of quiescent cells into proliferating stage and that results in suppression of a group of proteins that are implicated in the maintenance of differentiated cells. The basic helix-loop-helix, bHLH, family of DNA binding proteins such as Ngn, NeuroD, and Mash1, are the primary targets for Id1 which upon dysregulation may promote neuronal cell injury and apoptosis. Our preliminary data suggest that activation of Id1 gene by Tat is mediated via a novel regulatory pathway that includes critical transcription factors such as Egr1, C/EBP and SP1, all of which physically and functionally interact with Tat. In Aim one of this project we will perform a series of comprehensive functional and structural studies to unravel the molecular mechanisms involved in activation of Id1 by Tat in neuronal cells. In Aim two, we will investigate the importance of Id1, whose expression is elevated by Tat, in neuronal cell cycle, control of expression and activity of factors controlling cell entry into cell cycle and checkpoints such as p21, p16, pRb, and various cyclins. Furthermore, the role of Tat-induced overproduction of Id1 on the expression and activity of bHLH will be assessed. The outcome of these studies will provide a new information on the pathways which are affected by HIV-1 Tat, and will assist to improve our effort for developing strategies against HIV-1 induced neuronal cell injury.

描述（由申请人提供）：HIV-1侵入中枢神经系统（CNS）可诱导多种临床异常，包括痴呆，也称为HIV-1相关性痴呆（HAD）。组织学上，患有神经系统疾病的艾滋病患者的脑活检显示出广泛的异常，最显著的是神经元细胞丢失。没有神经元感染表明病毒诱导神经元细胞损伤的间接作用。大量研究结果表明，脑内感染的巨噬细胞、小胶质细胞和星形胶质细胞表达和分泌多种细胞蛋白，包括细胞因子和免疫调节剂，参与了神经细胞的损伤。除了细胞因子之外，病毒调节蛋白达特由于其独特的能力而受到关注，所述独特的能力是被感染的细胞分泌、进入未感染的细胞并在没有病毒感染的情况下改变细胞基因的表达。此外，达特蛋白已被证明具有神经毒性活性，最有可能通过失调信号传导途径，这是神经元细胞存活的关键。通过使用PC 12神经元细胞模型以及原代大鼠神经元细胞，我们证明了达特刺激Id基因的表达，Id基因是一种已知的抑制神经元细胞分化的细胞蛋白。通过影响控制细胞周期的几种因子的表达和活性，促进静止细胞不按计划进入增殖阶段，并导致抑制一组与维持分化细胞有关的蛋白质。碱性螺旋-环-螺旋，bHLH，DNA结合蛋白家族，如Ngn，NeuroD和Mash 1，是Id 1的主要靶点，其在失调时可能促进神经元细胞损伤和凋亡。我们的初步数据表明，达特激活Id 1基因是通过一个新的调控途径，包括关键的转录因子，如Egr 1，C/EBP和SP 1，所有这些物理和功能上的相互作用与达特。在本项目的目的一中，我们将进行一系列全面的功能和结构研究，以阐明达特在神经元细胞中激活Id 1的分子机制。在目的二中，我们将研究Id 1的重要性，其表达被达特提高，在神经元细胞周期中，控制细胞进入细胞周期的因子的表达和活性的控制，以及检查点，如p21，p16，pRb，和各种细胞周期蛋白。此外，将评估Tat诱导的Id 1过度产生对bHLH表达和活性的作用。这些研究的结果将为HIV-1达特影响神经元细胞的途径提供新的信息，并将有助于改善我们开发抗HIV-1诱导的神经元细胞损伤的策略的努力。