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 逆转录病毒的研究导致了重要发现，并引发了人们对基本细胞生物学的见解 包括细胞信号的机制，基因表达的调节和最终的细胞转化 和癌症。我们在该PPG中的合作工作重点是HTLV-1，这主要与成人有关 T细胞白血病（ATL）和神经系统疾病在一小部分受感染的个体中，对于 比较研究相关但非致病性HTLV-2。 HTLV-1的疾病进展已经 归因于税收，尽管我们和其他人已经假设并提供了另一个病毒基因称为的数据 HBZ在恶性过程中起着至关重要的作用。 HBZ是从存在于 HTLV-1前病毒基因组的3'末端的反义链。我们通过 与Ratner博士（项目4）和Niewiesk博士（核心C）的合作表明HBZ减少了税收介导的 病毒转录，通过改变 多个细胞因子，是体内病毒持久性和肿瘤细胞器官浸润所必需的。这 激动人心的工作为这个高度综合的延续项目提供了基础，旨在确定 HBZ转化和疾病。我们的总体假设是发现 HBZ并定义HBZ与税收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，最终将提供用于误导HTLV-1的治疗靶向方法 主机的持久性。该项目和核心提到的这项高度集成的竞争续约提案 下面的合作有两个具体目标。 特定的目标1将剖析HBZ专注于HBz mRNA活动的作用机理（项目2，4， 和核心b），HBZ翻译后修饰（项目2和核心B）的功能作用，以及对 细胞蛋白相互作用和途径重点是JUN，NFKB和干扰素（IRF-1，IRF-7） 法规（项目2、3和4）。 特定的目标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HBZ与税收中的相互作用 转化和肿瘤诱导过程。