Oncogenesis of retrovirus induced-glioma and the development of animal model

所谓的禽类胶质瘤（星形细胞瘤）的病因和病理特征尚未确定。我们认为病因是禽白血病病毒（ALV）的a亚群。本课题旨在阐明家禽胶质瘤诱导病毒（FGV）的致病性，分析env基因和LTR基因在其神经致病性中的分子生物学作用。首先，对实验感染FGV的鸡进行病理检查。虽然其他分离的alv通常诱导造血肿瘤，但FGV可能在大脑和心脏中复制，并诱导非化脓性脑炎和心肌炎，神经系统的脑膜瘤，小脑发育不全以及星形细胞瘤。基因组序列分析表明FGV与几种病毒株结合。与其他alv相比，LTR的U3区域有少量缺失和一些点突变（EMBL， GenBank和DDBJ核苷酸序列数据库，登录号为AB112960）。LTR启动子活性也有细微差异，可能与胶质肿瘤的诱导有关。此外，51例受影响的脑组织的组织病理学显示存在星形细胞弥漫性增殖的组织学变异，表明该疾病实体应命名为鸡“逆转录病毒诱导的星形细胞瘤”。为了检测FGV LTR启动子在体内的活性，在LTR启动子的控制下，制备了13株表达一种转基因的转基因小鼠，并利用逆转录-聚合酶链反应监测每株小鼠mRNA的表达，分析其组织特异性。结果表明，尽管LTR在体内作为泛特异性启动子，但FGV LTR启动子能够驱动稳定的转基因表达，特别是在中枢神经系统和睾丸中。

The cause and pathological features of so-called fowl glioma (astrocytoma) had not been determined. We have suggested that the cause is a subgroup A of avian leukosis virus (ALV). The subject of this research project is to clarify the pathogenicity of fowl glioma-inducing virus (FGV) and to analyze the molecular biological role of env gene and LTR in the neuropathogenicity. At first, chickens experimentally infected with FGV were pathologically examined. Whereas other isolated ALVs generally induce hematopoietic neoplasms, FGV was likely to replicate especially in brain and heart and induced nonsuppurative encephalitis and myocarditis, perineurioma, cerebellar hypoplasia as well as astrocytoma in nervous system. Genome sequence analysis suggested FGV to be combined with several virus strains. The U3 region of the LTR had a few deletions and several point mutations compared to that of other ALVs (EMBL, GenBank, and DDBJ nucleotide sequence databases under the accession number AB112960). The promoter activity of LTR also showed subtle differences, which may be related to the induction of glial neoplasm. In addition, histopathology of the 51 affected brains suggested the presence of a histological variant composed of diffuse proliferation of astrocytes and indicated that the disease entity should be named "retrovirus-induced astrocytoma" of chickens. To examine the promoter activity of FGV LTR in vivo, 13 lines of transgenic mice expressing a transgene under the control of the LTR promoter were generated and the tissue specificity of the expression was analyzed by monitoring mRNA in each line using the reverse transcription-polymerase chain reaction. The results indicated that the FGV LTR promoter was capable of driving a stable transgene expression especially in the central nervous system and testis although the LTR acted as a panspecific promoter in vivo.