Macrophage, Meth, HIV and Histones: An Interplay

摘要： HIV-1感染和滥用药物对整个机体的功能具有破坏性影响。的 巨噬细胞是单核吞噬细胞类细胞的主要成员，是先天性巨噬细胞的关键部分。 免疫系统因为巨噬细胞也是HIV的目标，是生产性病毒感染的储存库， 作为将感染传播到许多器官的媒介，它对疾病进程的影响是核心的。的复杂性 滥用药物使艾滋病毒感染进一步复杂化和加剧。甲基苯丙胺（Methamphetamine） 之所以选择它，是因为它是一种在吸毒人群中越来越受欢迎的药物， 或者有感染艾滋病的风险治疗这些人是一个非常复杂的过程，因为它必须针对两个实体 本质上是完全不同的。作为系统生物学的两条主要途径，全局分析技术和 大型数据集的计算处理，成熟，它成为可行的开始分析数据， 多变量实验先前的还原论方法排除了在这种水平上进行实验。 复杂性此外，尽管有大量的研究工作，但分子机制的广泛情况 巨噬细胞在HIV-1感染和/或甲基苯丙胺使用的复杂环境中的潜在功能还远未达到 被理解总之，我们假设，合并蛋白质组学，代谢组学和 计算分析到一个全面的系统生物学方法来研究调控 机制将提供独特的信息，这将导致确定新的范例， 议员如何应对艾滋病毒感染和/或冰毒侵害的复杂环境。我们预计 有针对性的分析，计算生物学和生物信息学分析将发现新的和未报告的 MP监管机制，并将模拟功能网络，可以通过重点和 靶向实验，因为它们存在于来自非人灵长类动物的离体材料中。更好地理解 MP的表观遗传调控将使我们能够确定病毒攻击下主要靶细胞的弱点， 感染和冰毒提出了三个具体目标：1。为了表征表观遗传因素的网络， 由HIV感染和/或Meth. 2.表征 HIV感染和/或Meth治疗诱导的MDM细胞内和细胞外代谢组的变化 由转录因子和调节因子（TF&R）的调节功能的改变引起;和3.到 在离体人体样本中验证整合的复杂蛋白质组学和代谢组学数据， 艾滋病毒和/或冰毒如何调节MP的范例。

Abstract: HIV-1 infection and drug of abuse have devastating effects on function of the entire organism. The macrophage is the prime member of the mononuclear phagocyte class of cells and a key part of innate immunity system. Because the macrophage is also a target of HIV, a reservoir of productive viral infection and a vehicle to spread infection to many organs, its impact on the course of disease is central. The complexity of HIV infection is further complicated and intensified by use of drugs of abuse. Methamphetamine (Meth) was chosen since it is a drug with increasing popularity among the drug-abusing population and used by those with, or at risk for HIV. Treatment of these individuals is a very complex process because it has to target two entities that are quite different in nature. As two main avenues of Systems Biology, global profiling techniques and computational processing of large data sets, mature, it becomes feasible to start analyzing data from multivariate experiments. Prior reductionist approaches precluded performing experiments at this level of complexity. Moreover, despite substantive research efforts, the broad picture of molecular mechanisms underlying functions of macrophages in the complex environment of HIV-1 infection and/or Meth use is far from being understood. Summarizing, we hypothesize that merging proteomics, metabolomics and computational analyses into a comprehensive systems biology approach to investigate regulatory mechanisms will provide unique information that will lead to the identification of new paradigms on how the MP responds to the complex environment of HIV infection and/or Meth insult. We expect that targeted profiling, computational biology, and bioinformatic analyses will uncover new and unreported mechanisms of MP regulation and will model functional networks that can be validated by focused and targeted experiments as they exist in ex vivo material from non-human primates. Better understanding of the epigenetic regulation of MP will enable us to define weak points of the major target cell under insult of viral infection and Meth. Three specific aims are proposed: 1. To characterize the networks of epigenetic factors in human monocyte derived macrophage (MDM) induced by HIV infection and/or Meth. 2. To characterize changes in intra- and extracellular metabolomes of MDM induced by HIV infection and/or Meth treatment resulting from alterations in regulatory functions of transcription factors and regulators (TF&R) and 3. To validate integrated complex proteomic and metabolomic data in ex vivo human samples to build new paradigms of how HIV and/or Meth regulate the MP.