Retrovirus Models of Lymphocyte Transformation/Disease

描述（由申请人提供）：研究复杂逆转录病毒如人类t淋巴细胞嗜1型病毒（HTLV-1）和人类免疫缺陷病毒（HIV）的调节和辅助蛋白和病毒编码酶，为定义病毒诱导转化的机制和细胞生物学的基本范式提供了基础知识。该计划项目拨款（PPG）申请的重点是使用逆转录病毒模型来阐明控制淋巴细胞转录调节的基本细胞机制。这一认识将使人们对病毒在复制过程中的致病机制与抗逆转录病毒诱导的癌症的治疗方式之间的界面有新的认识。每个项目都将显著扩大PPG实验室之间正在进行的合作努力。项目#1旨在了解p12I和p30II在t淋巴细胞转录调控和HTLV-1体内感染建立中的重要作用。项目#2将扩展定义HTLV Rex磷酸化作用的基础知识，从而了解该病毒蛋白如何用于研究t淋巴细胞中的mRNA转运。项目#3将通过使用新的控制元件和逆转录病毒载体来测试逆转录病毒细胞相互作用的转录后控制。Project #4定义了甲状旁腺激素相关蛋白在ATL及其相关的副肿瘤综合征、恶性肿瘤的体液性高钙血症中的作用和调控。项目#5继续俄亥俄州立大学和华盛顿大学圣路易斯分校之间的富有成效的合作，以确定调节蛋白Tax在淋巴细胞增殖和病毒相关疾病中的作用。三个交互核心支持PPG：管理/生物统计学，成像和动物模型。PPG的总体目标是使用逆转录病毒模型来确定决定淋巴细胞增殖和相关疾病的重要机制，以及测试消除逆转录病毒致癌作用的创新模式。

DESCRIPTION (provided by applicant): The study of regulatory and accessory proteins and virus encoded enzymes of complex retroviruses such as human T-lymphotropic virus type 1 (HTLV-1) and human immunodeficiency virus (HIV) and have provided fundamental knowledge to define mechanisms of viral-induced transformation and basic paradigms of cell biology. This Program Project Grant (PPG) application is focused on using retrovirus models to elucidate basic cellular mechanisms governing transcriptional regulation of lymphocytes. This understanding will lead to new insights into the interface between pathogenic mechanisms of the virus during its replication and therapeutic modalities against retroviral-induced cancer. Each project will significantly expand ongoing collaborative efforts between the PPG laboratories. Project #1 is seeking to understand the essential role of p12I and p30II in transcriptional regulation in T-lymphocytes and in the establishment of HTLV-1 infection in vivo. Project #2 will extend the fundamental knowledge that defines the role of phosphorylation in HTLV Rex and thereby learn how this viral protein can be used to study mRNA transport in T-lymphocytes. Project #3 will test post-transcriptional control of retrovirus cell interaction through the use of novel control elements and retroviral vectors. Project #4 defines the role and regulation of parathyroid hormone related protein in ATL and its associated paraneoplastic syndrome, humoral hypercalcemia of malignancy in human and animal models. Project #5 continues the productive collaboration between The Ohio State University and Washington University, St. Louis to determine the role of the regulatory protein Tax in lymphocyte proliferation and virus-associated disease. Three interactive cores support the PPG: Administration/Biostatistics, Imaging, and Animal Models. The overall goal of the PPG is to use retrovirus models to define important mechanisms that determine lymphocyte proliferation and associated disease, as well as to test innovative modalities to ablate the effects of retroviral carcinogenesis.