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：
10415186
负责人：
Patrick Lee Green
金额：
$ 29.41万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-21 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10415186
关键词：
Adult Precursor T Lymphoblastic Leukemia Adult T-Cell Leukemia/Lymphoma Animal Model Animals Attenuated Binding Binding Proteins Biological Assay Bone Diseases Cancer Model Cell Proliferation Cell Survival Cells Cellular biology Clustered Regularly Interspaced Short Palindromic Repeats Collaborations DNA Double Strand Break Data Disease Disease Progression Foundations Funding Future Gene Expression Gene Expression Regulation Genes Genetic Transcription Genome Human T-lymphotropic virus 1 Human T-lymphotropic virus 2 IRF1 gene In Vitro Individual Infection Knock-out Knowledge Malignant - descriptor Malignant Neoplasms Mediating Messenger RNA Modeling Nitric Oxide Synthase Oncoproteins Oryctolagus cuniculus Osteolytic Outcome Pathogenesis Pathogenicity Pathway interactions Persons Play Process Protein Interaction Mapping Proteins Proteomics RNA Retroviridae Role Signal Pathway Signal Transduction Structure TOP1 gene Taxes Transactivation Transforming Growth Factor beta Transgenic Mice Transgenic Organisms Translating Viral Viral Genes Viral Vector Virus Diseases Work chronic infection design effective therapy experimental study humanized mouse in vivo insight leukemia/lymphoma leukemogenesis metaplastic cell transformation nervous system disorder novel p65 prevent protein expression senescence tax Genes therapeutic target tumor ubiquitin-protein ligase vector virus host interaction

项目摘要

PROJECT SUMMARY – PROJECT 1 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 (HAM/TSP) in a small percentage of infected individuals. 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. Our presented data, as well as the work of others, indicate that hbz is multi-functional, playing important roles in both the RNA and protein form throughout infection and establishment of latency. We have extended our proposed work through PPG collaborations to better understand the manner in which hbz promotes proliferative and survival activity in cells. Proteomic analyses identified a panel of cellular proteins that distinctly interact with hbz RNA and HBZ protein. Functional characterization of these interactions are the next critical steps and the basis for this highly integrative continuation project designed to further define the role of hbz in transformation and disease. Our overall hypothesis is that uncovering the mechanism of actions of hbz RNA and HBZ protein will provide important insight into HTLV-1 cellular transformation and disease and ultimately will provide means for therapeutic targeting to eradicate HTLV-1 persistence in the host. This highly integrated proposal as referenced by Project and Core collaborations below has two Specific Aims. Aim 1 will dissect the mechanism(s) of action of hbz RNA and determine its contributions to the pathogenic process. We hypothesize that cellular protein interaction with hbz mRNA 2o structure translates to cell signaling pathways important for viral persistence and cellular proliferation. Our new proteomics data has identified, and we further validated, distinct cellular proteins that bind hbz mRNA. This aim will utilize in vitro approaches (Projects 2 and 3, Cores Admin/Biostats and Viral Vector) to identify the hbz RNA interactive region and determine the functional role of cellular binding proteins in cell proliferation. We will use in vivo approaches (Animal Core) to understand the contribution of the RNA and interactive proteins in the establishment of persistence and tumor formation. Aim 2 will dissect the mechanism(s) of action of HBZ protein and determine its contributions to HTLV-1 pathobiology. Our new proteomics data has identified, and we further validated, distinct cellular proteins that bind HBZ. In vitro approaches (Project 3, Cores Admin/Biostats and Viral Vector) including protein interaction mapping, cellular proliferation assays, and cellular transformation assays will be utilized to identify the HBZ interactive region and the functional role of key cellular binding proteins in HTLV-1 pathobiology. In vivo approaches (Animal Core, Project 2) will be used to determine the contribution of these HBZ interactive proteins in the establishment of persistence, infected cell survival, and tumor formation.

项目摘要 - 项目1 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细胞信号传导的机制，基因表达的调节以及最终的细胞转化和癌症。我们在PPG中的合作工作重点介绍HTLV-1，这主要与成人T细胞有关在受感染的个体中，白血病（ATL）和神经系统疾病（HAM/TSP）。疾病 HTLV-1的进展归因于税收，尽管我们和其他人已经假设并提供了数据该病毒基因称为HBz，在恶性过程中起着至关重要的作用。我们提出的数据作为他人的工作，表明HBZ是多功能的，在RNA和蛋白质中都起着重要作用整个感染和延迟的建立。我们已经通过PPG扩展了拟议的工作协作以更好地了解HBZ促进细胞中的增殖和存活活性的方式。蛋白质组学分析鉴定了一系列与HBZ RNA和HBz蛋白相互作用的细胞蛋白。这些相互作用的功能表征是此高度整合的下一个关键步骤和基础延续项目旨在进一步定义HBZ在转化和疾病中的作用。我们的整体假设是，发现HBz RNA和HBZ蛋白的作用机理将提供重要的深入了解HTLV-1细胞转化和疾病，最终将提供治疗的含义靶向主机中的radiodicate HTLV-1持久性。该项目所引用的这个高度集成的提案下面的核心协作具有两个具体目标。 AIM 1将剖析HBZ RNA作用的机制并确定其对致病过程的贡献。我们假设细胞蛋白与 HBZ mRNA 2O结构转化为细胞信号传导途径，对病毒持久性和细胞很重要增殖。我们的新蛋白质组学数据已经确定，我们进一步验证了结合的不同细胞蛋白 HBZ mRNA。该目标将利用体外方法（项目2和3，核心/生物稳定和病毒载体）确定HBz RNA相互作用区域并确定细胞结合蛋白在细胞中的功能作用增殖。我们将使用体内方法（动物核）来了解RNA的贡献和在建立持久性和肿瘤形成中的互动蛋白。 AIM 2将剖析机制 HBZ蛋白的作用，并确定其对HTLV-1病理生物学的贡献。我们的新蛋白质组学数据具有确定，我们进一步验证了结合HBz的不同细胞蛋白。体外方法（项目3，核心管理员/生物量和病毒载体）包括蛋白质相互作用映射，细胞增殖分析和细胞转换测定将用于识别HBz交互区域和钥匙的功能作用 HTLV-1病理生物学中的细胞结合蛋白。体内方法（动物核心，项目2）将用于确定这些HBz互动蛋白在建立持久性，感染细胞中的贡献生存和肿瘤形成。