(m) TOR signaling in EBV-associated lymphomas

与爱泼斯坦-巴尔病毒(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其常见。在HIV感染中，它们代表艾滋病的定义条件，通常表现为高级别、高阶段的恶性肿瘤，经常累及包括口腔在内的结外部位。EBV相关淋巴瘤(EBV-AL)在EBV编码基因的表达程度上具有相当的异质性，因此，EBV在其发病中所起的明显作用。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称为TOR或m(哺乳动物)TOR的丝氨酸/苏氨酸激酶]，在低纳摩尔剂量下，在体外和体内深刻抑制培养的EBV阳性B细胞的生长(M.Majewski等人)。2000年，M.Majewski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对TOR抑制剂的敏感性，以及EBV在诱导TOR信号转导中的可能作用，仍有待阐明。本研究将探讨TOR激活的机制和TOR及其作用， EBV-AL发病机制中的信号转导途径具体地说，我们将确定： 1.TOR信号通路在未培养的患者来源的淋巴瘤细胞中的激活状态 2.TOR在淋巴瘤细胞中的激活机制 3.TOR信号在淋巴瘤细胞转化中的作用 这些研究可能导致EBV相关疾病的新诊断和治疗方法 艾滋病毒/艾滋病和其他患者中的淋巴瘤。

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.