Regulation of gHV68-induced B cell proliferation

描述(申请人提供)：不受控制的增殖是恶性病变的标志，包括B细胞淋巴瘤。小鼠伽玛疱疹病毒MHV68类似于人类伽马疱疹病毒，感染并潜伏在B细胞中，并在感染动物中引起淋巴增生性疾病和B细胞淋巴瘤。MHV68可诱导小鼠脾细胞增殖和B细胞活化。MHV68诱导细胞增殖的机制尚不清楚。MHV68诱导的增殖和淋巴肿大之间的联系还没有被研究过，但很可能存在。建议的研究侧重于了解MHV68驱动的B细胞增殖所涉及的病毒和宿主因素。目标1中提出的体外实验将检验这样一种假设，即MHV68驱动的脾细胞增殖是由于B细胞的增殖，并由分泌的有丝分裂原介导。在特定的目的中，将使用2个MHV68突变体来确定在体外与B细胞增殖有关的MHV68基因产物(S)。为了验证体外B细胞增殖所需的MHV68蛋白(S)也在MHV68诱导的体内淋巴瘤发生中起作用的假说，将使用MHV68淋巴肿大的模型。

DESCRIPTION (provided by applicant): Uncontrolled proliferation is a hallmark of malignant lesions, including B cell lymphomas. Murine gammaherpesvirus MHV68, similar to human gammaherpesviruses, infects and remains latent in B cells and causes lymphoproliferative disorders and B cell lymphomas in infected animals. MHV68 induces proliferation of murine splenocytes and activation of B cells. The mechanisms of MHV68-induced cellular proliferation are not clear. The connection between MHV68-induced proliferation and lymphomagenesis has not been examined, but is likely to exist. Proposed studies focus on the understanding of viral and host factors involved in MHV68-driven B cell proliferation. In vitro experiments proposed in Aim 1 will test the hypothesis that MHV68-driven splenocyte proliferation is due to proliferation of B cells and is mediated by a secreted mitogen. In specific aim 2 MHV68 mutants will be used to determine a MHV68 gene product(s) that is responsible for B cell proliferation in vitro. A model of MHV68 lymphomagenesis will be used in Specific Aim 3 to test the hypothesis that MHV68 protein(s) required for B cell proliferation in vitro also play a role in MHV68-induced lymphomagenesis in vivo.