Interaction of HTLV-1 Tax & Hbz in Transformation

HTLV-1 税的相互作用

基本信息

批准号：
10403617
负责人：
Lee Ratner
金额：
$ 21.65万
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10403617
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

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 税收与 Hbz 在转型中的相互作用抽象的人类 T 细胞白血病病毒 1 型 (HTLV-1) 是难治性 T 细胞淋巴增殖性疾病的病因，指定为成人 T 细胞白血病淋巴瘤 (ATLL)。 HTLV-1 编码两个癌基因，Tax 和 Hbz，每个基因在转基因小鼠中诱导 T 细胞淋巴瘤。 Tax 是一种有效的转录反式激活蛋白还会导致遗传不稳定。然而，Tax 具有免疫原性，并且其表达在注射后下调。 ATLL 发展。 Hbz RNA 和蛋白质具有促进 T 细胞活化和增殖的独立活性。 Hbz 在整个感染过程中持续表达。我们假设 Tax 的主要作用是 T 细胞淋巴瘤起始，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来检验这一假设并阐明这些作用的潜在分子机制癌基因及其相互作用。在我们的 Tax+Hbz- 转基因小鼠中，Tax 受到多西环素诱导型启动子。 T 细胞淋巴瘤在多西环素存在下发生，并在多西环素存在下消退缺席。在我们的 Tax-Hbz+ 转基因小鼠中，全长 Hbz RNA 和功能表位标记的 Hbz 蛋白是在活化的 T 细胞中表达并诱导 T 细胞淋巴瘤。双转基因 Tax+Hbz+ 小鼠发育肿瘤比任一单一转基因模型更快。这些动物有成像标记来监测多西环素诱导和税收活动。在目标 1 中，我们将通过以下方式比较全外显子基因组学和转录组学： Tax+Hbz-、Tax-Hbz+ 和 Tax+Hbz+ 小鼠的 RNAseq 均维持强力霉素以确定是否税收会导致我们的小鼠模型中的遗传不稳定性以及经常发生的基因是否会发生突变 ATLL 发生突变。我们将使用 RNAseq 来识别负责每个转基因独特特征的基因，以及与单转基因动物相比，双转基因动物是否存在明显的改变。瞄准 2、我们将撤回多西环素以确定肿瘤是否在Tax+Hbz+动物中继续增殖，但是在 Tax+Hbz- 动物中进行回归，并通过 RNAseq 确定负责不同生物学的基因结果。我们将把我们的转录组改变与 ATLL 中的转录组改变进行比较。在目标 3 中，我们将使用 shRNA 或转基因模型中确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 ATLL 细胞系的小鼠模型。这些研究将为税收和税收如何提供新的见解。 Hbz 介导转化，这可能会导致 ATLL 的新疗法和新生物标志物的鉴定对于这种疾病。