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：
8303230
负责人：
BASSEL E SAWAYA
金额：
$ 36.34万
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/8303230
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.

描述（由申请人提供）：在过去的十年中，小型非编码RNA分子（〜20-30核苷酸NT]）已成为真核基因组表达和功能的关键调节剂。调节可以在几个重要水平的基因组功能上进行，包括染色质结构，染色体分离，转录，RNA处理，RNA稳定性和翻译。基础调节的中心主题是，小型RNA充当特异性因素，这些因素将效应蛋白引导到通过碱基配对相互作用靶向核酸分子。经过广泛研究的小型RNA类别是SMAL干扰RNA（siRNA）和microRNA（miRNA）。虽然miRNA被定义为内源基因的调节剂，但siRNA被描述为响应外国或侵入性核酸（例如病毒，转座子和转基因）的基因组完整性的捍卫者。两类RNA在体细胞谱系中作用在各种真核物种中。有人提出，病毒感染和疾病预后也可能由小RNA塑造。这促使我们假设艾滋病毒感染改变了内源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，我们启动了研究，以检查病毒蛋白（HIV-1 TAT）对miRNAS表达的影响，因为其特征（例如从感染细胞中释放出来，也受到各种细胞类型的吸收）。因此，TAT有可能在感染和未感染的细胞中造成损害。有趣的是，使用神经元的原发性培养物，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）的表达，以及其靶基因（例如CREB）及其在下面模型中所示的神经元功能所涉及的。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HIV-1相关神经疾病的细胞因子的参与。这些研究的结果将有助于预防和/或延迟在艾滋病患者中观察到的神经元失调和疾病。