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

描述（由申请人提供）：在过去的十年中，小的非编码RNA分子（~ 20 - 30个核苷酸nt）已经成为真核生物基因组表达和功能的关键调节因子。这种调控可以发生在几个重要的基因组功能水平上，包括染色质结构、染色体分离、转录、RNA加工、RNA稳定性和翻译。调控的核心主题是小rna作为特异性因子，通过碱基配对相互作用直接影响蛋白靶向核酸分子。被广泛研究的小rna的类别是小干扰rna （sirna）和微rna （miRNAs）。虽然mirna被定义为内源性基因的调节因子，但sirna被描述为应对外来或侵入性核酸（如病毒、转座子和转基因）时基因组完整性的捍卫者。这两类rna在广泛的真核生物物种的体细胞谱系中起作用。有人认为，病毒感染和疾病结果也可能由小rna决定。这促使我们假设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，我们开始研究一种病毒蛋白（HIV-1 Tat）对miRNAs表达的影响，因为它具有从感染细胞中释放和被不同细胞类型摄取的特征。因此，Tat有可能对感染和未感染的细胞造成损害。有趣的是，使用神经元、神经元细胞系、人脑组织和Tat转基因小鼠大脑的原代人培养物，我们的数据显示Tat影响了几种mirna（例如miR-34a）及其靶基因（例如CREB）的表达，这些mirna参与神经元功能，如下图所示。基于此，我们建议通过体外和体内动物模型来研究这些受调控的mirna以及细胞因子在HIV-1相关神经系统疾病中的作用。这些研究的结果将有助于预防和/或延缓在艾滋病患者中观察到的神经失调和疾病。

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.