Project 4: Tumorigenic Effects of Tax

项目 4：税收的致瘤效应

基本信息

批准号：
8742042
负责人：
Lee Ratner
金额：
$ 41.95万
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/8742042
关键词：
1-Phosphatidylinositol 3-Kinase Address Adult T-Cell Leukemia/Lymphoma Animal Genetics Animal Model Antibodies Apoptosis Binding Biological Assay Cancer Etiology Cancer Model Cell Death Cell Extracts Cells Classification Clinical Research Clinical Trials Clonality Code Defect Development Digestion Dimerization Disease Epitopes Future Gene Expression Gene Targeting Goals Human T-lymphotropic virus 1 Immunodeficient Mouse Infection Leucine Zippers Lymphoma Mass Spectrum Analysis Mediating Methodology Modeling Molecular Molecular Target Monitor Multiple Myeloma Mus Mutation Nuclear Oncogene Proteins Outcome PDZ protein Pathogenesis Pathway interactions Phosphoric Monoester Hydrolases Physiological Prevention Protein Binding Protein Precursors Proteins Proteomics Proviruses Research Resistance Retroviridae Role Signal Transduction Solid Neoplasm T-Lymphocyte Taxes Techniques Testing Therapeutic Therapy Clinical Trials Trypsin Up-Regulation Variant Viral Virus base cell transformation deep sequencing expression cloning human cord blood CD34+ cell innovation leukemia/lymphoma lymphocyte proliferation mouse model mutant neoplastic cell novel pre-clinical programs research study tax Gene Products tumor tumor initiation tumorigenesis tumorigenic

项目摘要

PROJECT SUMMARY HTLV-1 is the etiological agent of adult T-cell leukemia lymphoma (ATLL). ATLL cells are characterized by constitutive NF¿B activation, a key feature of other lymphomas, myeloma, and solid tumors. The Tax oncoprotein is the key viral determinant for NF¿B activation. Our previous studies showed that the classical and especially, the alternative NF¿B pathways were critical in conferring resistance to apoptosis. Our primary hypothesis is that Tax activation of NF¿B is critical for tumorigenesis, particularly the alternative (alt) NF¿B pathway. The current study will use innovative, physiological lymphoma models to define the role in tumorigenesis of each NF¿B pathway and identify the key regulators of the NF¿B pathway. Aim 1. Aim 1. To assess the role of alt NF¿B activity in Tax-mediated transformation A new humanized mouse model is used for HTLV-1 infection and lymphoma development. We will use viral variants expressing Tax mutants with defects in activating the alternative NF¿B pathway or both NF¿B pathways, in order to define their role in disease pathogenesis. A novel high-throughput viral integration assay is used to monitor clonality of infected cells in these experiments. Aim 2. To identify and characterize Tax interactive proteins that mediate alt NF¿B activation We will identify Tax interactive proteins that mediate alt NF¿B pathway activation. Proteins that interact with wild type but not mutant Tax will then be characterized using shRNAs to assess their effect on Tax induced cleavage of alt NF¿B precursor protein, p100, as well as effects on proliferation and apoptosis of HTLV-1 transformed cells in culture and immunodeficient mice. It is expected that the information these physiologically relevant mouse models will identify key target genes that may be inhibited in therapeutic trials of ATLL or other lymphomas.

项目概要 HTLV-1 是成人 T 细胞白血病淋巴瘤 (ATLL) 的病原体，其特征是 ATLL 细胞。本构 NF¿ B 激活是其他淋巴瘤、骨髓瘤和实体瘤的一个关键特征。癌蛋白是 NF 的关键病毒决定因素¿我们之前的研究表明，经典的B激活。尤其是替代 NF¿ B 途径对于赋予我们的主要细胞凋亡抵抗力至关重要。假设是税收激活 NF¿ B 对于肿瘤发生至关重要，尤其是替代 (alt) NF¿乙目前的研究将使用创新的生理性淋巴瘤模型来定义其作用。每个 NF 的肿瘤发生？ B 通路并确定 NF 的关键调节因子¿ B途径。目标 1. 目标 1. 评估替代 NF 的作用¿ B 税收介导转型活动一种新的人源化小鼠模型用于 HTLV-1 感染和淋巴瘤发展。我们将使用病毒。表达 Tax 突变体的变体在激活替代 NF 方面存在缺陷¿ B 途径或两者 NF¿乙途径，以确定它们在疾病发病机制中的作用。用于监测这些实验中受感染细胞的克隆性。目标 2. 识别和表征介导 alt NF 的 Tax 相互作用蛋白¿ B激活我们将鉴定介导 alt NF 的 Tax 相互作用蛋白¿ B 途径激活的蛋白质。然后将使用 shRNA 对野生型而非突变型 Tax 进行表征，以评估其对 Tax 诱导的影响 alt NF 的裂解¿ B前体蛋白、p100以及对HTLV-1增殖和凋亡的影响培养物和免疫缺陷小鼠中的转化细胞。预计这些生理相关小鼠模型的信息将识别关键目标基因 ATLL 或其他淋巴瘤的治疗试验可能会受到抑制。