MOLECULAR BASIS FOR THE PATHOGENICITY OF MURINE RETROVIRUSES

鼠逆转录病毒致病性的分子基础

• 批准号: 3838442
• 负责人: S K RUSCETTI
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3838442
• 关键词: Friend leukemia; erythroid stem cell; erythroleukemia; gene expression; genetic recombination; laboratory mouse; molecular cloning; molecular oncology; transcription factor; viral leukemogenesis; viral myelinopathy; virus cytopathogenic effect; virus envelope; virus genetics; virus protein

Using mouse model systems, studies have been carried out to elucidate the mechanisms by which certain retroviruses cause leukemia and neurological disease and to identify the viral and host genes that are involved. Studies on the ME26 virus have shown that the virus transforms hematopoietic cells by a novel mechanism. The viral transforming protein was shown to transcriptionally activate an erythroid-specific transcription factor, GATA-1, and then to cooperate with GATA-1 to transactivate the erythropoietin (Epo) receptor. Studies on the Friend spleen focus-forming virus have concentrated on understanding the mechanism by which the viral envelope protein abrogates the Epo requirement of erythroid cells. The protein appears to interact with the Epo receptor, and both of these proteins have been expressed at high levels using baculovirus vectors to facilitate further studies. To understand the molecular basis for the resistance of mice to erythroleukemia induced by Friend MuLV, an endogenous, modified polytropic retrovirus has been molecularly cloned, which is expressed in Rmcf-r, but not Rmcf-s mice. Studies are in progress to determine if the expression of the env gene of this clone can block replication of polytropic viruses and inhibit F-MuLV-induced erythroleukemia. Studies on PVC-211, a variant of Friend MuLV, which causes neurological disease, but not leukemia in mice, have shown that sequences within the env gene are responsible for the pathological changes in the central nervous system, although other sequences in the 5' one-third of the viral genome are required for rapid and complete progression of disease. The failure of PVC-211 to cause erythroleukemia was shown to be due to changes in the U3 region of the LTR.

使用小鼠模型系统，已经进行了研究以阐明 某些逆转录病毒引起白血病和神经系统疾病的机制 疾病，并确定病毒和宿主基因的参与。 对ME26病毒的研究表明， 通过一种新的机制。 病毒转化蛋白 显示转录激活红细胞特异性 转录因子加塔-1，然后与加塔-1合作， 反式激活促红细胞生成素（Epo）受体。 对Friend脾病灶形成病毒的研究集中在 了解病毒包膜蛋白消除的机制 红系细胞的Epo需求。 这种蛋白质似乎 与Epo受体，这两种蛋白质已经表达， 使用杆状病毒载体进行更高水平的表达，以便于进一步研究。 为了了解小鼠抵抗 Friend MuLV诱导的红白血病，一种内源性的，修饰的多向性 逆转录病毒已被分子克隆，它在Rmcf-r中表达，但 而不是Rmcf-s小鼠。 研究正在进行中，以确定表达是否 该克隆的env基因的50%可以阻断嗜多性病毒的复制 并抑制F-MuLV诱导的红白血病。 研究PVC-211，朋友MuLV的变体，导致神经系统疾病 疾病，但不是小鼠白血病，已经表明， env基因与中枢神经系统的病理变化有关 神经系统，虽然其他序列在5 '三分之一的病毒 基因组是疾病快速和完全进展所必需的。 的 PVC-211未能引起红白血病是由于 在LTR的U3区。