(m) TOR signaling in EBV-associated lymphomas

与EB病毒（EBV）相关的淋巴瘤在HIV/AIDS、器官移植和其他免疫缺陷患者中特别常见。在HIV感染中，它们代表AIDS定义性病症，并且通常表现为高级别、高阶段恶性肿瘤，经常涉及包括口腔在内的结节部位。EBV相关淋巴瘤（EBV-AL）在EBV编码基因的表达程度方面是相当异质的，因此，EBV在其模式发生中起着明显的作用。我们已经发现雷帕霉素及其衍生物RAD [两者都通过选择性抑制称为TOR或m（哺乳动物）TOR的丝氨酸/苏氨酸激酶起作用]，在低纳摩尔剂量下在体外和体内显著抑制培养的EBV阳性B细胞的生长（M. Maurisski et al. 2000，M. Mauriski等人，2003年）。然而，TOR抑制剂对淋巴瘤细胞的确切作用机制、各种类型EBV-AL中TOR抑制剂敏感性的频率以及EBV在诱导TOR信号传导中的假定作用仍有待阐明。本文提出的研究将研究TOR激活的机制和TOR及其作用， EBV-AL发病机制中的信号通路。具体而言，我们将确定： 1.未培养的患者源性淋巴瘤细胞中TOR信号通路的激活状态 2.淋巴瘤细胞中TOR激活的机制 3. TOR信号在淋巴瘤细胞转化中的作用 这些研究可能会导致新的诊断和治疗方法，以EBV相关的 艾滋病毒/艾滋病和其他患者的淋巴瘤。

Lymphomas that are associated with the Epstein-Barr virus (EBV) are particularly frequent in patients with HIV/AIDS, organ transplants and other immunodeficiencies. In the HIV infection they represent an AIDS defining condition and typically present as a high grade, high stage malignancy, frequently involving extranodal sites including oral cavity. The EBV-associated lymphomas (EBV-AL) are rather heterogeneous in regard to the extent of expression of the EBV-encoded genes and, consequently, the apparent role EBV plays in their patogenesis. We have found that rapamycin and its derivative RAD [both act by selectively inhibiting a serine/threonine kinase called TOR or m(mammalian)TOR ], profoundly supress at low nanomolar doses the growth of cultured EBV-positive B-cells in vitro and in vivo (M. Majewski et al. 2000, M. Majewski et al., 2003). However, the exact mechanism of action of the TOR inhibitors on the lymphoma cells, the freqquency of TOR inhibitor sensitivity in various types of EBV-AL, and the putative role of EBV in induction of theTOR signaling remain to be elucidated. The studies proposed here will examine the mechanisms of TOR activation and and role of TOR and its, signaling pathwayin the pathogenesis of EBV-AL. Specifically, we will determine the: 1. activation status of the TOR signaling pathways in uncultured, patient-derived lymphoma cells 2. mechanisms of TOR activation in the lymphoma cells 3. role of TOR signaling in cell transformation of the lymphoma cells These studies may result in novel diagnostic and therapeutic approaches to the EBV-associated lymphomas in HIV/AIDS and other patients.