Retrovirus Models of Lymphocyte Transformation and Disease

描述（由申请人提供）：P01 CA100730的竞争性更新申请寻求资金，以继续研究高度整合的逆转录病毒模型，以阐明定义淋巴细胞转化和疾病的基本细胞机制。逆转录病毒的研究为定义细胞转化机制以及细胞生物学的基本范式提供了基础和关键的知识。相互作用的性质、已建立的合作记录，以及构成PPG延续计划的单个项目和核心的重点，直接支持NCI的战略计划和目标。在过去的四年中，我们的目标是通过64篇同行评审的手稿实现的，其中70%是PPG研究者之间的互动。该计划的继续将通过相互关联的目标扩大已建立的相互作用，以确定控制淋巴细胞从激活到永生和转化转变的关键事件。项目1利用逆转录病毒提供新的见解，了解它们如何改变转录和DNA损伤/修复信号，以建立持续感染并为细胞转化奠定基础。项目2 （Dr. Green）将定义逆转录病毒的新型转录后机制，并与Dr. Lairmore （Project 1）合作，比较测试病毒复制和淋巴细胞转化中的每种蛋白质。项目3与多个PPG研究人员合作，将研究逆转录病毒和关键生长控制基因的基本翻译控制机制。项目4（博士）Weilbaecher，华盛顿大学和Rosol，俄亥俄州立大学)将他们的专业知识与PPG研究人员结合起来，研究骨微环境在溶骨和成骨细胞肿瘤模型中的作用。项目5（拉特纳博士）继续两所大学之间的高度动态合作，使用独特的转基因小鼠模型来测试炎症微环境在致癌作用中的作用。PPG由五个互动项目和三个高度支持的核心组成。每个项目都涉及两个中心组成部分，涉及通过逆转录病毒调节淋巴细胞信号和基因表达或改变导致转化和副肿瘤疾病的细胞微环境。PPG的相互作用性质将为支持转化研究提供基本假设，以确定针对逆转录病毒诱导的淋巴瘤的治疗干预，并完善动物模型以确定逆转录病毒诱导的癌症的分子决定因素。

DESCRIPTION (provided by applicant): This competitive renewal application of P01 CA100730 seeks funds to continue the study of highly integrated retrovirus models to elucidate essential cellular mechanisms that define lymphocyte transformation and disease. The study of retroviruses has provided fundamental and critical knowledge for defining the mechanisms of cell transformation as well as fundamental paradigms of cell biology. The interactive nature, established record of collaborations, and focus of the individual projects and cores that constitute the proposed PPG continuation are directly supportive of NCI's strategic plans and goals. Our goals were realized with robust productivity over the last four years demonstrated by 64 peer-reviewed manuscripts 70% interactive between PPG investigators. The continuation of the Program will extend upon the established interactions through inter-related goals to define critical events that control the transition of lymphocytes from activation through immortalization and transformation. Project 1 uses retroviruses to provide novel insights into how they alter transcription and DNA damage/repair signaling to establish persistent infections and set the stage for cellular transformation. Project 2 (Dr. Green) will define novel post-transcriptional mechanisms of retroviruses and working together with Dr. Lairmore (Project 1), will comparatively test each protein in viral replication and lymphocyte transformation. Project 3 working collaboratively with multiple PPG investigators will examine the fundamental translational control mechanisms in both retroviruses and in crucial growth control genes. Project 4 (Drs. Weilbaecher, Washington University and Rosol, Ohio State University) combine their expertise with PPG investigators to study the role of bone microenvironment in osteolytic and osteoblastic tumor models. Project 5 (Dr. Ratner) continues the highly dynamic collaborations between each University to test the contribution of the inflammatory microenvironment in carcinogenesis using unique transgenic mouse models. The PPG consists of five interactive Projects and three highly supportive Cores. Each project is related to two central components involving the regulation of lymphocyte signaling and gene expression by retroviruses or alterations of the cellular microenvironment leading to transformation and paraneoplastic disease. The interactive nature of the PPG will provide rationale hypotheses to support translational studies to define therapeutic intervention against retrovirus-induced lymphoma and refine animal models to determine molecular determinants of retrovirus-induced cancer.