Interaction of HTLV-1 Tax & Hbz in Transformation

HTLV-1 税的相互作用

基本信息

批准号：
10189192
负责人：
Lee Ratner
金额：
$ 18.41万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-10 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10189192
关键词：
ANXA5 gene Adult Adult T-Cell Leukemia/Lymphoma Animal Model Animals Apoptosis Apoptotic Biochemical Biological CREB1 gene CRISPR screen Cell Line Cell Proliferation Characteristics Clonal Expansion Development Disease Doxycycline Epitopes Exons Future Gene Expression Gene Targeting Genes Genetic Genetic Transcription Genomics Human T-lymphotropic virus 1 IRF4 gene Individual Infection Lead Length Lentivirus Long Terminal Repeats Lymphomagenesis Lymphoproliferative Disorders Maintenance Malignant Neoplasms Malignant lymphoid neoplasm Mediating Modeling Molecular Monitor Mus Mutate Mutation Oncogenes Oncoproteins Pathologic Pathway interactions Patients Peptide Initiation Factors Physiological Prevention Proliferating Proteins Proviruses RNA Refractory Regulation Reporter Role Sequence Analysis Signal Transduction Small Interfering RNA Stains Structural Genes T-Cell Activation T-Cell Lymphoma T-Lymphocyte Taxes Testing Tetanus Helper Peptide Trans-Activators Transcript Transcription Coactivator Transcription Factor AP-1 Transgenes Transgenic Animals Transgenic Mice Transgenic Model Transgenic Organisms Tumor Promoters Viral Viral Oncogene Virus Virus Diseases Virus Replication Withdrawal Work beta catenin imaging biomarker immunogenic in vivo insight mouse model non-invasive monitor novel novel marker novel therapeutics promoter senescence small hairpin RNA tax Gene Products tax Genes transcriptome sequencing transcriptomics treatment strategy tumor tumor growth tumor initiation tumor progression tumorigenesis tumorigenic

ANXA5 gene Adult Adult T-Cell Leukemia/Lymphoma Animal Model Animals Apoptosis Apoptotic Biochemical Biological CREB1 gene CRISPR screen Cell Line Cell Proliferation Characteristics Clonal Expansion Development Disease Doxycycline Epitopes Exons Future Gene Expression Gene Targeting Genes Genetic Genetic Transcription Genomics Human T-lymphotropic virus 1 IRF4 gene Individual Infection Lead Length Lentivirus Long Terminal Repeats Lymphomagenesis Lymphoproliferative Disorders Maintenance Malignant Neoplasms Malignant lymphoid neoplasm Mediating Modeling Molecular Monitor Mus Mutate Mutation Oncogenes Oncoproteins Pathologic Pathway interactions Patients Peptide Initiation Factors Physiological Prevention Proliferating Proteins Proviruses RNA Refractory Regulation Reporter Role Sequence Analysis Signal Transduction Small Interfering RNA Stains Structural Genes T-Cell Activation T-Cell Lymphoma T-Lymphocyte Taxes Testing Tetanus Helper Peptide Trans-Activators Transcript Transcription Coactivator Transcription Factor AP-1 Transgenes Transgenic Animals Transgenic Mice Transgenic Model Transgenic Organisms Tumor Promoters Viral Viral Oncogene Virus Virus Diseases Virus Replication Withdrawal Work beta catenin imaging biomarker immunogenic in vivo insight mouse model non-invasive monitor novel novel marker novel therapeutics promoter senescence small hairpin RNA tax Gene Products tax Genes transcriptome sequencing transcriptomics treatment strategy tumor tumor growth tumor initiation tumor progression tumorigenesis tumorigenic

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项目摘要

Interaction of HTLV-1 Tax & Hbz in Transformation Abstract Human T-cell leukemia virus type 1 (HTLV-1) is the cause of a refractory T cell lymphoproliferative disorder, designated adult T-cell leukemia lymphoma (ATLL). HTLV-1 encodes two oncogenes, Tax and Hbz, each of which induces T cell lymphoma in transgenic mice. Tax is a potent transcriptional trans activator protein that also induces genetic instability. However, Tax is immunogenic and its expression is down-regulated after ATLL develops. Hbz RNA and protein have separable activities that promote T cell activation and proliferation. Hbz is continuously expressed throughout infection. We hypothesize that the predominant role of Tax is T cell lymphoma initiation, and the predominant role of Hbz is a T cell lymphoma promoter. We developed three animal models to test this hypothesis and elucidate the underlying molecular mechanisms for the roles of these oncogenes and their interactions. In our Tax+Hbz- transgenic mice, Tax is under the regulation of a doxycycline inducible promoter. T cell lymphomas develop in the presence of doxycycline, and regress in its absence. In our Tax-Hbz+ transgenic mice, full length Hbz RNA and functional epitope tagged Hbz protein are expressed in activated T cells and induce T cell lymphomas. Double transgenic Tax+Hbz+ mice develop tumors more rapidly than either single transgenic model. These animals have imaging markers to monitor doxycycline induction and Tax activity. In Aim 1, we will compare full exon genomics and transcriptomics by RNAseq of Tax+Hbz-, Tax-Hbz+, and Tax+Hbz+ mice all maintained on doxycycline in order to determine if Tax induces genetic instability in our mouse model and whether mutations occur in genes that are frequently mutated in ATLL. We will use RNAseq to identify genes responsible for the unique features of each transgene, and if there are distinct alterations in double transgenic animals compared to single transgenic animals. In Aim 2, we will withdraw doxycycline in order to determine if tumors continue to proliferate in Tax+Hbz+ animals, but regress in Tax+Hbz- animals, and to determine, by RNAseq, the genes responsible for the different biological results. We will compare our transcriptomic alterations to those in ATLL. In Aim 3, we will use shRNAs or lentivirus expression of key genes identified in the transgenic models, to test high priority candidates from our murine model in short-term cultured ATLL cell lines. These studies will provide new insights into how Tax and Hbz mediate transformation, which could lead to new therapies for ATLL and identification of novel biomarkers for this disease.

HTLV-1税和HBZ在转型中的相互作用抽象的人类T细胞白血病1型（HTLV-1）是难治性T细胞淋巴增生性疾病的原因，指定的成年T细胞白血病淋巴瘤（ATLL）。 HTLV-1编码两个癌基因，税收和HBZ，每一个这会诱导转基因小鼠中T细胞淋巴瘤。税是一种有效的转录反式激活蛋白还引起遗传不稳定。但是，税收是免疫原性的，其表达在 ATLL发展。 HBZ RNA和蛋白质具有可分离的活性，可促进T细胞活化和增殖。 HBZ在整个感染过程中持续表达。我们假设税收的主要作用是T细胞淋巴瘤的启动，HBz的主要作用是T细胞淋巴瘤启动子。我们开发了三个动物模型检验该假设并阐明了这些假设的基本分子机制癌基因及其相互作用。在我们的税收+HBZ-转基因小鼠中，税收受强力霉素诱导启动子。 T细胞淋巴瘤在强力霉素的存在下发展，并在其中回归缺席。在我们的Tax-HBz+转基因小鼠中，全长HBz RNA和功能性表位标记为HBZ蛋白在活化的T细胞中表达并诱导T细胞淋巴瘤。双转基因税+ HBZ+小鼠发展肿瘤比任何一个单个转基因模型都要快。这些动物有成像标记以监测强力霉素诱导和税收活动。在AIM 1中，我们将通过比较完整的外显子基因组学和转录组学税务+HBz-，税收HBZ+和税收+HBz+小鼠的RNASEQ均维持在强力霉素上，以确定是否是否税收在我们的小鼠模型中引起遗传不稳定，以及在基因中是否发生突变在ATLL中突变。我们将使用RNASEQ识别负责每个转基因独特特征的基因，如果与单个转基因动物相比，双转基因动物有明显的改变。目标 2，我们将撤回强力霉素，以确定肿瘤是否继续在税收+ HBz+动物中泛滥，但是税收+HBZ-动物的回归，并通过RNASEQ确定负责不同生物学的基因结果。我们将将转录组的变化与ATLL中的转录组进行比较。在AIM 3中，我们将使用shrnas或在转基因模型中鉴定的关键基因的慢病毒表达，以测试我们的高优先级候选者短期培养的ATLL细胞系中的鼠模型。这些研究将为税收和如何税提供新的见解 HBZ介导转化，这可能导致新的ATLL疗法和新型生物标志物的识别对于这种疾病。