Retrovirus Models of Cancer

癌症逆转录病毒模型

• 批准号: 8742035
• 负责人: Patrick Lee Green
• 金额: $ 179.1万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/8742035
• 关键词: Adult T-Cell Leukemia/Lymphoma; Affect; Animal Model; Animals; Apoptotic; Biometry; Biostatistics Core; Budgets; CREB1 gene; Cancer Model; Cell Aging; Cell Cycle; Cell Death; Cell physiology; Cells; Cellular biology; Code; Collaborations; Complex; Critiques; Development; Diagnosis; Disease; Enzymes; Erinaceidae; Event; FOS gene; Funding; Gene Expression; Genotype; Goals; Growth; Homeostasis; Human; Human T-lymphotropic virus 1; Human T-lymphotropic virus 2; IL2RA gene; Immune system; In Vitro; Infection; Institution; Knowledge; Laboratories; Leadership; Link; Lymphocyte Activation; Lymphoma; Lymphoproliferative Disorders; MAP Kinase Gene; Maintenance; Malignant Neoplasms; Manuscripts; Mediating; Messenger RNA; Modeling; Molecular; Molecular Cloning; Mouse Strains; Mus; Mutation; Nature; Neoplasms; Oncogenes; Oncogenic Viruses; Oryctolagus cuniculus; Osteoclasts; Osteogenesis; Pathogenesis; Pathologist; Pathway interactions; Peer Review; Phenotype; Physicians; Premalignant Cell; Process; Productivity; Program Research Project Grants; Protein Analysis; Proteins; Proteomics; Provirus Integration; RNA; Recommendation; Research; Research Personnel; Resource Sharing; Retroviridae; Retroviridae Infections; Role; Scientist; Signal Pathway; Signal Transduction; Signaling Protein; Site; Surface; Syndrome; T-Lymphocyte; Taxes; Testing; Therapeutic Intervention; Transgenic Mice; Tumor Expansion; Vertebrates; Veterinarians; Viral; Viral Oncogene; Virus; Work; activating transcription factor; anticancer research; bone; bone turnover; cancer type; cell age; cell immortalization; cell transformation; effective therapy; human FRAP1 protein; human subject protection; human tissue; in vivo Model; leukemia/lymphoma; leukemogenesis; lymphocyte proliferation; neoplastic; new therapeutic target; notch protein; programs; public health relevance; receptor; transcription factor; translational study; tumor; tumor initiation; tumorigenic

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.

描述（由申请人提供）：本计划项目拨款竞争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同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，并与已建立的动物模型（HIS 小鼠、转基因小鼠、兔子）联系起来，以测试疾病的分子决定因素。每个项目负责人都会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件相互依赖。项目 1（Green）与项目 4（Ratner）合作将鉴定 Hbz RNA 和蛋白质的细胞相互作用成分，并将使用体外和体内模型来确定 Hbz 和 Tax 之间的相互作用，以揭示肿瘤发生、促进或维持所需的机制和途径。项目 2 (Kvaratskhelia) 与项目 1 (Green) 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：Tax 和 Hbz 表达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，以增加破骨细胞吸收并减少骨形成，这将有利于肿瘤在骨中的扩张。项目 4 (Ratner) 与项目 1 合作将鉴定和表征 Tax 相互作用蛋白，以确定替代 NF?B 激活的作用机制，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 5 年里，该 PPG 的研究人员实现了强劲的生产力，77 篇同行评审的手稿证明了这一点； PPG 研究人员之间的合作率为 43%。这一竞争性的更新 PPG 组建并整合了一支由医师科学家、基础科学家、实验动物兽医和病理学家组成的独特团队，并将支持交互式基础研究和转化研究，以确定针对 HTLV-1 相关白血病/淋巴瘤和其他相关癌症的转化机制和治疗干预。