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.

项目概要 逆转录病毒的研究取得了重要发现，并深入了解了基础细胞生物学 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。我们在该 PPG 中的合作重点是 HTLV-1，它主要与成人相关 一小部分感染者会出现 T 细胞白血病 (ATL) 和神经系统疾病，并且 比较研究相关但非致病性的HTLV-2。 HTLV-1 导致的疾病进展 尽管我们和其他人已经假设并提供了另一种病毒基因（称为 Hbz 在恶性过程中起着至关重要的作用。 Hbz 由存在于 HTLV-1 原病毒基因组 3' 末端的反义链。我们通过以下方式扩展了我们的工作 与 Ratner 博士（项目 4）和 Niewiesk 博士（核心 C）合作，表明 HBZ 减少了税收中介 病毒转录，通过改变转录活性来促进 HTLV-1 感染细胞的增殖 多种细胞因子，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 Hbz 的转化和疾病。我们的总体假设是揭示作用机制 Hbz 以及定义 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，最终将为根除 HTLV-1 的治疗靶向提供手段 宿主的坚持。项目和核心引用的这个高度集成的竞争性更新提案 以下合作有两个具体目标。 具体目标 1 将剖析 Hbz 的作用机制，重点关注 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 细胞蛋白相互作用和通路，重点关注 Jun、NFkB 和干扰素（IRF-1、IRF-7） 监管（项目 2、3 和 4）。 具体目标 2 将结合体外（转化测定）和体内（转基因和人源化小鼠） 方法（项目 2、3、4 和核心 C）确定蜂窝中 HBZ 和 Tax 之间的相互作用 转化和肿瘤诱导过程。