Role of microRNA in HIV associated neurological disorder (HAND).

microRNA 在 HIV 相关神经系统疾病 (HAND) 中的作用。

基本信息

批准号：
8213267
负责人：
BASSEL E SAWAYA
金额：
$ 35.09万
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：
2011
资助国家：
美国
起止时间：
2011-07-18 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8213267
关键词：
AIDS Dementia Complex Acquired Immunodeficiency Syndrome Affect Alzheimer&apos s Disease Animal Model Autopsy BDNF gene Base Pairing Behavioral Biological Markers Brain CCL2 gene CREB1 gene Categories Cell physiology Cells Cerebrum Characteristics Chromatin Structure Chromosome Segregation Data Defect Development Diagnostic Disease Disease Outcome Disease Progression Functional RNA Gene Expression Gene Targeting Genes Genetic Transcription Genetic Variation Genome HIV HIV Infections HIV encephalitis HIV-1 Human Human Cell Line In Vitro Lead Learning Length Life Cycle Stages MicroRNAs Mitochondria Modeling Nerve Degeneration Neuraxis Neurites Neurocognitive Neurodegenerative Disorders Neurodevelopmental Disorder Neurologic Neuronal Plasticity Neurons Nucleic Acids Nucleotides Opportunistic Infections Outcome Study Parkinson Disease Pathology Patients Pattern Peripheral Nervous System Diseases Phenotype Play Proteins RNA Processing RNA Stability Regulation Role Shapes Small RNA Specificity Stress Symptoms Synaptic plasticity TNF gene Testing Therapeutic Agents Transgenes Transgenic Mice Translations Viral Viral Proteins Virus Virus Diseases base brain tissue cell type chemokine cytokine in vivo nervous system disorder neuron loss neuronal survival new therapeutic target prevent prognostic research study response tat Protein uptake

项目摘要

DESCRIPTION (provided by applicant): Over the last decade, small non-coding RNA molecules (~ 20 - 30 nucleotide nt]) have emerged as critical regulators in the expression and function of eukaryotic genomes. The regulation can occur at several important levels of genome function including chromatin structure, chromosome segregation, transcription, RNA processing, RNA stability, and translation. The central theme underlying regulation is that the small RNAs serve as specificity factors that direct effector proteins to target nucleic acid molecules via base-pairing interactions. The categories of small RNAs that have been investigated extensively are the smal interfering RNAs (siRNAs) and microRNAs (miRNAs). While miRNAs have been defined as regulators of endogenous genes, siRNAs are described as defenders of genome integrity in response to foreign or invasive nucleic acids such as viruses, transposons, and transgenes. Both categories of RNAs act in somatic lineages in a broad range of eukaryotic species. It has been suggested that virus infections and disease outcome may also be shaped by small RNAs. This has prompted us to hypothesize that HIV infection alters the endogenous miRNA expression patterns, thereby contributing to neuronal deregulation and AIDS dementia. In support of this hypothesis, we initiated studies to examine the impact of a viral protein (HIV-1 Tat) on miRNAs expression due to its characteristic features such as release from the infected cells and also uptake by diverse cell types. Hence, Tat has the potential to cause damage both in infected and uninfected cells. Interestingly, using primary human cultures of neurons, neuronal cell line, human brain tissues and brains of Tat-transgenic mice, our data show that Tat affected the expression of several miRNAs (e.g. miR-34a) as well as their target genes (e.g. CREB) that are involved in neuronal functions as shown in the model below. Based on that, we propose to investigate the involvement of these regulated miRNAs as well as the cellular factors in the context of HIV-1 associated neurological disease by using in vitro and in vivo animal models. Outcome from these studies will serve to prevent and/or delay neuronal deregulation and disorders observed in AIDS patients. PUBLIC HEALTH RELEVANCE: A significant number of patients infected with HIV-1 progress slowly to HIV-associated neurocognitive disorders (HAND). We demonstrated that HIV-1 Tat protein plays a role in neuronal degeneration through regulation of microRNA and their target genes that could lead to HAND development. Therefore, we wil investigate whether involvement of miRNAs and their target genes promote disease progression. These data will ultimately serve to enhance our understanding of the progression of HAND.

描述（由申请人提供）：在过去的十年中，小非编码RNA分子（约20-30个核苷酸nt]）已成为真核基因组表达和功能的关键调节因子。这种调节可以发生在基因组功能的几个重要水平上，包括染色质结构、染色体分离、转录、RNA 加工、RNA 稳定性和翻译。调节的中心主题是小RNA作为特异性因子，通过碱基配对相互作用指导效应蛋白靶向核酸分子。已被广泛研究的小RNA类别是小干扰RNA (siRNA) 和微小RNA (miRNA)。虽然 miRNA 被定义为内源基因的调节剂，但 siRNA 被描述为基因组完整性的捍卫者，以响应外来或侵入性核酸（例如病毒、转座子和转基因）。这两类 RNA 在广泛的真核物种的体细胞谱系中发挥作用。有人提出，病毒感染和疾病结果也可能是由小RNA决定的。这促使我们推测 HIV 感染改变了内源性 miRNA 表达模式，从而导致神经元失调和艾滋病痴呆。为了支持这一假设，我们发起了研究，以检查病毒蛋白 (HIV-1 Tat) 对 miRNA 表达的影响，因为它具有诸如从受感染细胞中释放以及被不同细胞类型摄取等特征。因此，Tat 有可能对受感染和未受感染的细胞造成损害。有趣的是，利用人类原代培养物的神经元、神经元细胞系、人脑组织和 Tat 转基因小鼠的大脑，我们的数据表明 Tat 影响了几种 miRNA（例如 miR-34a）及其靶基因（例如 CREB）的表达。）涉及神经元功能，如下图所示。基于此，我们建议通过使用体外和体内动物模型来研究这些受调节的 miRNA 以及细胞因子在 HIV-1 相关神经系统疾病中的参与情况。这些研究的结果将有助于预防和/或延迟艾滋病患者中观察到的神经元失调和疾病。公共卫生相关性：大量感染 HIV-1 的患者缓慢进展为 HIV 相关神经认知障碍 (HAND)。我们证明了 HIV-1 Tat 蛋白通过调节 microRNA 及其靶基因在神经元变性中发挥作用，从而导致 HAND 发育。因此，我们将研究 miRNA 及其靶基因的参与是否会促进疾病进展。这些数据最终将有助于增强我们对 HAND 进展的理解。