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

项目1：HTLV-1 Hbz在转化和疾病中的作用

• 批准号: 8742039
• 负责人: Patrick Lee Green
• 金额: $ 33.38万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-23 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8742039
• 关键词: Adult T-Cell Leukemia/Lymphoma; Animal Model; Attenuated; Binding; Biochemical; Biological Assay; C-terminal; CTLL-2 Assay; Cancer Model; Cells; Cellular Structures; Cellular biology; Collaborations; Comparative Study; Data; Disease; Disease Progression; Funding; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Human T-lymphotropic virus 1; Human T-lymphotropic virus 2; Hypercalcemia of Malignancy; IRF1 gene; Immune response; In Vitro; Individual; Infection; Infiltration; Interferons; Knock-out; Knowledge; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Messenger RNA; Modification; Mus; Nuclear Export; Oncogenic; Organ; Outcome; Pathogenesis; Pathway interactions; Phosphorylation; Play; Post-Translational Protein Processing; Process; Property; Proteins; Proteomics; RNA; Regulation; Repression; Retroviridae; Role; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; T-Lymphocyte; Taxes; Transcript; Transgenic Mice; Transgenic Organisms; Translating; Validation; Viral; Viral Genes; Virus; Virus Diseases; Work; base; cell immortalization; comparative; design; effective therapy; in vivo; in vivo Model; insight; metaplastic cell transformation; mouse model; neoplastic cell; nervous system disorder; novel; parathyroid hormone-related protein; promoter; protein expression; receptor; therapeutic target; tumor; tumor initiation; virus host interaction

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.

项目摘要 对逆转录病毒的研究带来了重要的发现，并使人们对基础细胞生物学有了深入的了解。 包括细胞信号传导机制、基因表达调控以及最终的细胞转化 和癌症我们在PPG中的合作工作集中在HTLV-1，它主要与成人相关。 T细胞白血病（ATL）和神经系统疾病在一小部分感染者中， 比较研究了相关但非致病性的HTLV-2。HTLV-1导致的疾病进展已被 归因于税收，虽然我们和其他人已经假设并提供数据，另一种病毒基因，称为 Hbz在恶性过程中起关键作用。Hbz由存在于Hbz基因中的功能性启动子编码。 HTLV-1前病毒基因组3'末端的反义链。我们将工作扩展到 与Ratner博士（项目4）和Niewiesk博士（核心C）合作，证明HBZ减少了税收介导的 病毒转录，促进HTLV-1感染细胞的增殖，通过改变转录活性， 多种细胞因子，并且是体内病毒持续存在和肿瘤细胞器官浸润所必需的。这 令人兴奋的工作为这个高度综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，揭示的行动机制， Hbz和定义Hbz和Tax之间的相互作用将为HTLV-1细胞提供重要的见解 转化和疾病，并最终将提供治疗靶向根除HTLV-1的手段 在主机上的持久性。这个高度集成的竞争性更新建议，如项目和核心参考 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活性（项目2，4， 和核心B），HBZ翻译后修饰的功能作用（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） （项目2、3、4）。 特异性目标2将在体外（转化试验）和体内（转基因和人源化小鼠）结合联合收割机 方法（项目2，3，4和核心C），以确定HBZ和税收之间的相互作用，在蜂窝 转化和肿瘤诱导过程。