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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结