HIV Induced Cellular Pathology

HIV 诱导的细胞病理学

• 批准号: 7020726
• 负责人: DAVID BALTIMORE
• 金额: $ 34.88万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7020726
• 关键词: MHC class I antigen; apoptosis; binding sites; biological signal transduction; cellular pathology; clinical research; cytotoxic T lymphocyte; flow cytometry; genetic transcription; human immunodeficiency virus 1; human tissue; laboratory mouse; leukocyte activation /transformation; molecular cloning; nuclear factor kappa beta; regulatory gene; tissue /cell culture; transcription factor; virus infection mechanism

DESCRIPTION (provided by applicant): The work proposed here has the long-term objective of contributing to the treatment of people with AIDS. We believe that if we develop a deep enough understanding of the molecular biology of HIV growth, we will uncover new targets for anti-retroviral therapy. The specific aims of the program are: 1) to understand the interaction of the NF-kappaB transcription factor with its binding site in the HIV genome and in cellular genes; 2) to understand whether RelB plays a negative role in the transcription of the HIV genome; 3) to identify and clone the genes for the proteins that are involved in making T cells a fertile soil for the growth of HIV. The proposal derives from the understanding that NF-kappaB is a critical transcription factor for expression of the HIV genome. For Aim 1, we will use novel technologies we have recently developed to determine exactly which components of the NF-kappaB family of proteins are responsible for the activity of the factor. We will also extend this work to the study of the cellular genes activated when T cells move from a quiescent state to an active state, a transition from resistance to HIV to permissiveness for viral growth. We wish to understand not only what proteins are involved but also why different genes use subtly different binding sites, and why different stimuli for NF-kappaB activation might lead to different protein requirements on a single DNA site. Aim 2 derives from our recent demonstration that one of the Rel- related subunits that compose NF-kappaB, RelB, plays a negative role in regulation. It can establish thresholds for activation as well as down-regulating transcription of genes that have responded to NF-kappaB. For Aim 3 we will attempt to find new proteins that function on the pathways that lead to activation of HIV permissivity and the concomitant receptor stimulation of latent HIV genomes. Although individual pathways are known to be used by particular activators, like T cell receptor stimulation or tumor necrosis factor, no one pathway is fully elucidated. For this we will use a novel screening methodology to find and ultimately characterize new proteins that lead to transcription of the HIV genome.

描述（由申请人提供）：这里提出的工作具有促进艾滋病患者治疗的长期目标。我们相信，如果我们对艾滋病毒生长的分子生物学有足够深入的了解，我们将发现抗逆转录病毒治疗的新靶点。该计划的具体目标是：1）了解NF-κ B转录因子与其在HIV基因组和细胞基因中的结合位点的相互作用; 2）了解RelB是否在HIV基因组的转录中起负面作用; 3）识别和克隆参与使T细胞成为HIV生长沃土的蛋白质的基因。该提议源于对NF-κ B是HIV基因组表达的关键转录因子的理解。对于目标1，我们将使用我们最近开发的新技术来确定NF-κ B蛋白家族的哪些组分负责该因子的活性。我们还将把这项工作扩展到研究T细胞从静止状态转变为活跃状态时激活的细胞基因，即从对HIV的抵抗转变为对病毒生长的宽容。我们不仅希望了解涉及哪些蛋白质，而且还希望了解为什么不同的基因使用微妙不同的结合位点，以及为什么不同的NF-κ B激活刺激可能导致单个DNA位点上不同的蛋白质需求。目的2源自我们最近的证明，即组成NF-κ B的Rel相关亚基之一RelB在调节中起负作用。它可以建立激活阈值以及下调对NF-κ B有反应的基因的转录。对于目标3，我们将试图找到新的蛋白质，其在导致HIV perceptor激活和潜伏HIV基因组的伴随受体刺激的途径上起作用。尽管已知特定的活化剂（如T细胞受体刺激或肿瘤坏死因子）使用单独的途径，但没有一种途径被完全阐明。为此，我们将使用一种新的筛选方法来发现并最终表征导致HIV基因组转录的新蛋白质。