Transcriptional Regulation, the Nuclear Proteome, and HIV/Meth/cART: From Profili

描述（由申请人提供）：HIV-1感染和药物滥用对整个生物体的功能具有破坏性影响。巨噬细胞是单核吞噬细胞类细胞的主要成员，是先天免疫系统的关键部分。由于巨噬细胞也是HIV的靶点，是生产性病毒感染的储存库，也是将感染传播到包括大脑在内的器官的媒介，因此它对疾病过程的影响至关重要。艾滋病毒感染的复杂性因滥用药物而进一步复杂化和加剧。选择甲基苯丙胺（METH）是因为它是一种在吸毒人群中越来越受欢迎的药物，并被艾滋病毒感染者或有感染艾滋病毒风险的人使用。对这些人的治疗是一个非常复杂的过程，因为它必须针对性质完全不同的两个实体。此外，HIV感染的终身cART治疗具有不良毒性作用。作为系统生物学的两个主要途径，全球分析技术和大型数据集的计算处理，成熟，它变得可行，开始分析数据从多变量实验（HIV/METH/cART）。先前的还原论方法排除了在这种复杂程度上进行实验。此外，尽管进行了大量的研究工作，但在HIV-1感染METH使用和/或cART的复杂环境中，巨噬细胞功能的分子机制的广泛情况还远未被理解。总之，我们假设系统生物学方法将提供独特的信息，这将导致识别新的范式，人类巨噬细胞如何在HIV感染，cART和METH的复杂环境中进行调节。我们希望我们的实验计划，通过使用组学技术，计算生物学和生物信息学分析，检查转录因子和其他核蛋白，将提供独特的信息，这将导致识别新的范式在人类巨噬细胞如何在HIV感染，cART和METH的复杂环境中进行调节。 公共卫生相关性：艾滋病毒转变为慢性疾病代表了治疗的巨大成功，但由于长期感染、抗逆转录病毒疗法的影响以及共存因素如影响包括脑和心血管系统在内的许多系统的药物滥用，也带来了许多新的临床问题。巨噬细胞是免疫系统的重要组成部分，在感染的持续和疾病的发生中起着重要作用。我们建议使用一种全球性的方法来研究HIV感染、药物滥用和抗逆转录病毒治疗对巨噬细胞的影响，这将使我们更好地了解疾病的分子机制，并提出新的治疗靶点。

DESCRIPTION (provided by applicant): 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 organs including the brain, 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. In addition, life-long cART treatment of HIV infection has adverse toxic effects. 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 (HIV/METH/cART). 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 METH use and/or cART is far from being understood. Summarizing, we hypothesize that the systems biology approach will provide unique information which will lead to identification of new paradigm how the human macrophage is regulated in the complex environment of HIV infection, cART and METH. We expect that our experimental plan, examining transcription factors and other nuclear proteins through the use of omic techniques, computational biology and bioinformatic analyses, will provide unique information which will lead to identification of new paradigms in how the human macrophage is regulated in the complex environment of HIV infection, cART and METH. PUBLIC HEALTH RELEVANCE: The transformation of HIV to a chronic disease represents a great success of therapy but has opened up a number of new clinical problems due to the long-term infection, effects of the anti-retroviral therapies, and coexisting factors such as drug abuse which affects many systems including the brain and cardiovascular systems. Macrophages, key component of immune system, play many roles in persistence of infection as well as disease causation. We propose to use a global approach to investigate the effects of HIV infection, drug abuse and anti-retroviral therapy on macrophage which should lead us to better understand molecular mechanisms of disease and propose new targets for therapy.