Retrovirus Models of Cancer

描述（由申请人提供）：本计划项目资助竞争性更新申请的最终目标是阐明逆转录病毒介导的疾病或调节淋巴细胞增殖/转化的细胞控制事件的机制。所有研究小组的主要共同点是共享使用我们实验室开发或表征的人类T细胞白血病病毒1型（HTLV-1）和HTLV-2的感染性分子克隆和衍生物，并连接到已建立的动物模型（HIS小鼠，转基因小鼠，兔子）以测试疾病的分子决定因素。每个项目负责人带来一个独特的项目，该项目与计划中其他项目和核心的组成部分相互依赖。项目1（绿色）与项目4（Ratner）合作，将鉴定Hbz RNA和蛋白质的细胞相互作用组分，并将使用体外和体内模型来确定Hbz和Tax之间的相互作用，以揭示肿瘤启动、促进或维持所需的机制和途径。项目2（Kvaratskhelia）与项目1（绿色）和项目4（Ratner）合作，将研究HTLV-1整合位点选择性对前病毒表达、细胞转化和最终发病机制的分子机制和作用。项目3（Weilbaecher和Rosol）将他们的专业知识与项目1、2和4相结合，以检验以下假设：表达Tax和Hbz的肿瘤中骨转换因子的肿瘤表达失调将重新编程ATL骨微环境，使其朝向破骨细胞再吸收增加和骨形成减少，这将有利于骨中的肿瘤扩张。项目4（拉特纳）与项目1合作，将确定和表征税收相互作用的蛋白质，以确定替代NF？B活化并确定该途径在Tax介导的转化中的作用。这四个高度集成的项目由三个独特的共享资源核心支持：核心A（管理和生物统计学），核心B（蛋白质组学和蛋白质分析）和核心C（动物模型使用和开发）。在过去的5年里，该PPG中的研究者实现了强大的生产力，如77篇同行评审的手稿所证明的; PPG研究者之间的合作占43%。这种竞争性的更新PPG组装并整合了一个独特的医生科学家，基础科学家，实验室动物兽医和病理学家团队，并将支持交互式基础和转化研究，以确定转化机制和针对HTLV-1相关白血病/淋巴瘤和其他相关癌症的治疗干预。

DESCRIPTION (provided by applicant): The ultimate goal of this Program Project Grant competiting renewal application is to elucidate mechanisms of retrovirus-mediated disease or cellular control events that regulate lymphocyte proliferation/ transformation. A primary common thread among all research groups is the shared use of infectious molecular clones and derivatives of human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2, developed or characterized in our laboratories, and links to established animal models (HIS mice, transgenic mice, rabbits) to test molecular determinants of disease. Each Project Leader brings a unique Project that is interdependent on components of other Projects and Cores in the Program. Project 1 (Green) in collaboration with Project 4 (Ratner) will identify cellular interacting components of both Hbz RNA and protein and will use in vitro and in vivo models to determine the interplay between Hbz and Tax to uncover the mechanisms and pathways necessary for tumor initiation, promotion or maintenance. Project 2 (Kvaratskhelia) in collaboration with Project 1 (Green) and Project 4 (Ratner) will investigate the molecular mechanisms and roles of HTLV-1 integration site selectivity for proviral expression, cell transformation and ultimately pathogenesis. Project 3 (Weilbaecher and Rosol) combines their expertise with Projects 1, 2, and 4 to test the hypothesis that dysregulated tumoral expression of bone turnover factors in Tax and Hbz expressing tumors will reprogram the ATL bone microenvironment towards increased osteoclast resorption and decreased bone formation, which will favor tumor expansion in bone. Project 4 (Ratner) in collaboration with Project 1 will identify and characterize Tax-interactive proteins to determine the mechanism of action of alternative NF?B activation and determine the role of this pathway in Tax-mediated transformation. These four highly integrated Projects are supported by three unique shared resource cores: Core A (Administration and Biostatistics), Core B (Proteomics and Protein Analysis) and Core C (Animal Model Use and Development). For the past 5 years, investigators within this PPG realized robust productivity as demonstrated by 77 peer-reviewed manuscripts; 43% collaborative between PPG investigators. This competing renewal PPG assembles and integrates a unique team of physician scientists, basic scientists, lab animal veterinarians, and pathologists and will support interactive basic and translational studies to define transformation mechanisms and therapeutic intervention against HTLV-1 associated leukemia/lymphomas and other related cancers.