(m) TOR signaling in EBV-associated lymphomas

与eb病毒（EBV）相关的淋巴瘤在艾滋病毒/艾滋病、器官移植和其他免疫缺陷患者中尤为常见。在HIV感染中，它们代表了艾滋病的定义条件，通常表现为高级别、高阶段的恶性肿瘤，经常累及结外部位，包括口腔。EBV相关淋巴瘤（EBV- al）在EBV编码基因的表达程度上是相当异质性的，因此，EBV在其发病机制中明显起作用。我们发现，雷帕霉素及其衍生物RAD[都是通过选择性抑制一种被称为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，在体外和体内都能显著抑制培养的ebv阳性b细胞的生长（m . Majewski et al. 2000, m . Majewski et al. 2003）。然而，TOR抑制剂对淋巴瘤细胞的确切作用机制、不同类型EBV- al中TOR抑制剂敏感的频率以及EBV在诱导它们的TOR信号传导中的假定作用仍有待阐明。本文提出的研究将探讨TOR的激活机制，以及TOR及其作用。

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.