Regulation of HIV infection by Methamphetamine and non-coding RNAs

描述（由申请人提供）：项目总结尽管非编码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学（包括HIV/AIDS）中的作用的认识仍存在重大差距。在这里，我们建议破译机制的非编码RNA，和它们相关的核糖核蛋白复合物，在调节HIV-1感染的主要巨噬细胞，特别是暴露于甲基苯丙胺（METH）。这些研究将建立在一组强大的初步数据的基础上，这些数据涉及几种短的和长的非编码RNA在HIV的调节和对METH的反应中。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复制方面的活性的重要见解。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点。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知识。公共卫生相关性：人类基因组中有相当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开始受到重视。在本申请中，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背景下。这些研究将使人们能够更全面地了解病毒发病机制的分子基础，并为艾滋病毒/艾滋病的治疗提供新的治疗机会。

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.