Project 1: Role of HTLV-1 Hbz in Transformation and Disease

项目总结 对逆转录病毒的研究导致了重要的发现，并导致了对基础细胞生物学的深入了解 包括细胞信号机制、基因表达调控以及最终的细胞转化。 和癌症。我们在PPG内的合作重点是HTLV-1，它主要与成人有关 T细胞白血病(ATL)和神经系统疾病在一小部分感染者中， 相关但非致病的HTLV-2的比较研究。HTLV-1的疾病进展一直是 归因于税收，尽管我们和其他人假设并提供了另一种病毒基因，称为 Hbz在恶变过程中起着关键作用。Hbz由存在于人类基因组中的功能启动子编码 HTLV-1前病毒基因组3‘端的反义链。我们把我们的工作扩展到 与Ratner博士(项目4)和Niewiesk博士(核心C)的合作表明HBZ减少了税收中介 病毒转录，通过改变HTLV-1转录活性促进HTLV-1感染细胞的增殖 多种细胞因子，是病毒持续存在和体内肿瘤细胞器官侵袭所必需的。这 激动人心的工作为这个高度整合的延续项目提供了基础，该项目旨在确定 转化和疾病中的Hbz。我们的总体假设是，揭示 Hbz和定义Hbz和Tax之间的相互作用将为了解HTLV-1细胞提供重要的见解 转化和疾病，最终将提供靶向治疗以消除HTLV-1的手段 在宿主中坚持不懈。此高度集成的竞争性续订建议书由项目和核心参考 下面的合作有两个具体目标。 具体目标1将剖析Hbz的作用机制，重点是Hbz mRNA的活性(项目2，4， 和核心B)，HBZ翻译后修改的功能作用(项目2和核心B)，以及对 细胞蛋白质相互作用和途径，重点是Jun、NFkB和干扰素(IRF-1、IRF-7) 条例(项目2、3和4)。 特殊目标2将结合体外(转化试验)和体内(转基因和人源化小鼠)。 确定HBZ和税收在蜂窝中的相互作用的方法(项目2、3、4和核心C) 转化和诱发肿瘤的过程。

PROJECT SUMMARY The study of retroviruses has resulted in important discoveries and led to insights into basic cell biology including mechanisms of cell signaling, regulation of gene expression, and ultimately cellular transformation and cancer. Our collaborative work within this PPG focuses on HTLV-1, which is associated primarily with adult T cell leukemia (ATL) and neurological disease in a small percentage of infected individuals, and for comparative studies the related but non pathogenic HTLV-2. Disease progression by HTLV-1 has been attributed to Tax, although we and others have hypothesized and provide data that another viral gene, termed Hbz, plays a critical role in the malignant process. Hbz is encoded from a functional promoter present in the antisense strand at the 3' terminus of the HTLV-1 proviral genome. We extended our work through collaborations with Dr. Ratner (Project 4) and Dr. Niewiesk (Core C) to show that HBZ reduces Tax-mediated viral transcription, promotes the proliferation of HTLV-1 infected cells by altering the transcriptional activity of multiple cellular factors, and is required for viral persistence and tumor cell organ infiltration in vivo. This exciting work provides the basis for this highly integrative continuation project designed to determine the role of Hbz in transformation and disease. Our overall hypothesis is that uncovering the mechanism of actions of Hbz and defining the interplay between Hbz and Tax will provide important insight into HTLV-1 cellular transformation and disease and ultimately will provide means for therapeutic targeting to erradicate HTLV-1 persistence in the host. This highly integrated competing renewal proposal as referenced by Project and Core collaborations below has two Specific Aims. Specific Aim 1 will dissect the mechanisms of action of Hbz focusing on Hbz mRNA activities (Project 2, 4, and Core B), the functional role of HBZ post-translational modification (Project 2 and Core B), and effects on cellular protein interactions and pathways with emphasis on Jun, and NFkB and interferon (IRF-1, IRF-7) regulation (Projects 2, 3 and 4). Specific Aim 2 will combine in vitro (transformation assays) and in vivo (transgenic and humanized mice) approaches (Project 2, 3, 4, and Core C) to determine the interplay between HBZ and Tax in the cellular transformation and tumor induction process.