Regulation of HIV infection by Methamphetamine and non-coding RNAs

尽管非编码rna构成了人类转录组的大部分，但我们对这些分子在大多数人类病理（包括HIV/AIDS）中的作用的了解仍然存在重大差距。在这里，我们建议破译非编码rna及其相关核糖核蛋白复合物在调节原代巨噬细胞HIV-1感染中的机制，特别是在暴露于甲基苯丙胺（METH）后。这些研究将建立在一组强有力的初步数据之上，这些数据暗示了几种短链和长链非编码rna参与了艾滋病毒的调控和对冰毒的反应。我们建议整合几种最先进的后基因组技术和新开发的实验方法，包括下一代测序和纳米颗粒递送系统，以提供对这些分子在促进和限制HIV复制中的活性的重要见解。这些分析旨在全面鉴定在原代人巨噬细胞中调节这些过程的非编码rna，并通过实验描绘其细胞或病毒靶标。总之，这些研究将为基于rna的宿主-病原体相互作用和抗病毒功能的分子和细胞机制提供重要的知识。人类基因组中包含的很大一部分基因不编码蛋白质，因此被称为“非编码rna”。它们在包括传染病在内的许多人类生理过程中的作用已开始得到重视。在这个应用中，我们建议阐明非编码rna在HIV感染中的作用，特别是在甲基苯丙胺滥用的情况下。这些研究将使人们更全面地了解病毒发病机制的分子基础，并为治疗HIV/AIDS提供新的治疗机会。

DESCRIPTION (provided by applicant): PROJECT SUMMARY Although non-coding RNAs comprise a majority of the human transcriptome, there remain critical gaps in our knowledge of the role of these molecules in most human pathologies, including HIV/AIDS. Here, we propose to decipher the mechanisms of non-coding RNAs, and their associated ribonucleoprotein complexes, in regulating HIV-1 infection of primary macrophages, particularly after exposure to Methamphetamine (METH). These studies will build on a powerful set of preliminary data that implicate several short and long non-coding RNAs in the regulation of HIV and response to METH. We propose to integrate several state-of-the-art post-genome technologies and newly developed experimental methodologies, including next generation sequencing and nanoparticle delivery systems, to provide important insights into the activity of these molecules in both promoting and restricting HIV replication. These analyses are designed to comprehensively identify non-coding RNAs that regulate these processes in primary human macrophages, and experimentally delineate their cellular or viral targets. Taken together, these studies will provide significant knowledge towards the molecular and cellular mechanisms underlying RNA-based host-pathogen interactions and antiviral functions. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE A significant proportion of the genes contained in the human genome do not encode proteins, and thus are termed 'non-coding RNAs'. Their role in a number of human physiological processes, including in infectious disease, are beginning to be appreciated. In this application, we are proposing to elucidate the role of non-coding RNAs in HIV infection, particularly in the context of Methamphetamine abuse. These studies will enable a more comprehensive understanding of the molecular basis for viral pathogenesis, and provide novel therapeutic opportunities for the treatment of HIV/AIDS.