Genetic Aspects Of Viral Oncogenesis In Wild Mouse Speci

各种野生小鼠和近交系小鼠在对逆转录病毒和逆转录病毒诱导的疾病的易感性方面彼此不同。这些差异是由于特定小鼠染色体基因的等位基因差异，我们一直在努力鉴定和表征参与这种抗性的几个小鼠基因： - 我们继续分析了在大多数小鼠中发现的一种血清脂蛋白因子，它能使白血病病毒失活。我们已经证明，这种因子的产生是由一个基因控制的。我们已经将该基因定位到小鼠10号染色体上的一个位置，并评估了候选基因Apof（载脂蛋白F）。这些实验表明，这种血清因子是由另一个紧密连锁的基因控制的，我们正在评估来自该区域的第二个候选基因。我们也在产生同源基因，以确定该因子的存在或缺失如何影响疾病进展。 - 我们继续努力表征耐药基因Rmcf，该基因负责对高致病性多变类白血病病毒的部分耐药性。我们已经克隆了一个染色体整合拷贝的病毒包膜连接到Rmcf基因座，并表明其表达与病毒抗性。这表明Rmcf抗性可能通过干扰机制介导。我们还在野生小鼠M.我们已经鉴定了一个相关的前病毒序列，现在正在克隆和表征。 - 我们正在研究野生老鼠的种类，M。spretus，M. musculus和M.对于病毒感染的易感性和对于新的白血病病毒。从麻省spicilegus我们已经分离了一种新的病毒变体，其在特定的小鼠细胞中诱导细胞病变变化。序列分析表明，该变体在形成受体结合位点的3个氨基酸之一中具有单个氨基酸取代。这种病毒在具有变异受体基因的细胞系中引起细胞病变效应，我们正在使用这种病毒-受体组合来检查病毒进入。在其他实验中，我们确定接种M.用实验室小鼠病毒感染Spretus小鼠导致重组病毒的产生。我们发现，重组病毒已获得了大量的包膜糖蛋白基因的取代，导致改变宿主范围的属性。我们还表明，在这只野生小鼠中发现的内源性前病毒是高度同源的，表明它们是最近获得的。 - 我们已经完成了与R博士的研究。鲤鱼中，我们检查了衰老倾向和抗性SAM小鼠品系的内源性病毒表达，发现具有加速衰老的品系共享一种特定的前病毒Akv1，该前病毒从这些品系的AKR小鼠祖先遗传而来。结果表明，该病毒在加速老化品系的胸腺、脾脏和脑组织中均有高表达。 - 最后，我们开发了几个对小鼠基因组分析和作图有用的资源。我们在与E博士的合作项目中使用了这些资源。Rassart鉴定致癌病毒的优选整合的新位点。

The various wild mice and inbred strains differ from one another in their susceptibility to retroviruses and retrovirus-induced diseases. These differences are due to allelic differences in specific mouse chromosomal genes, and we have been engaged in an ongoing effort to identify and characterize several mouse genes involved in this resistance: - We have continued our analysis of a serum lipoprotein factor found in most mice that inactivates leukemia viruses. We have demonstrated that production of this factor is controlled by a single gene. We have mapped this gene to a position on mouse chromosome 10 and evaluated a candidate gene, Apof (apolipoprotein F). These experiments showed that this serum factor is controlled by another closely linked gene, and we are in the process of evaluating a second candidate from this region. We are also generating congenics to determine how presence or absence of this factor affects disease progression. - We have continued our efforts to characterize the resistance gene Rmcf, which is responsible for partial resistance to the highly pathogenic polytropic class of leukemia viruses. We have cloned a chromosomally integrated copy of the viral envelope linked to the Rmcf locus, and shown that its expression is associated with virus resistance. This suggests that Rmcf resistance may be mediated through an interference mechanism. We have also identified a similar resistance phenotype in the wild mouse M. castaneus (termed Rmcf2) and we have identified an associated proviral sequence that is now being cloned and characterized. - We are examining the wild mouse species, M. spretus, M. musculus and M. spicilegus for susceptibility to virus infection and for novel leukemia viruses. From M. spicilegus we have isolated a novel virus variant that induces cytopathic changes in specific mouse cells. Sequence analysis has shown that this variant has a single amino acid substitution in one of the 3 amino acids that form the receptor binding site. This virus causes cytopathic effects in a cell line with a variant receptor gene and we are using this virus-receptor combination to examine viral entry. In other experiments we determined that inoculation of M. spretus mice with a laboratory mouse virus resulted in the generation of recombinant virus. We showed that the recombinant viruses had acquired substantial substitutions in the envelope glycoprotein gene that resulted in altered host range properties. We also showed that the endogenous proviruses found in this wild mouse are highly homologous suggesting they were recently acquired. - We have completed a study with Dr. R. Carp in which we examined the senescence prone and resistant SAM mouse strains for endogenous virus expression and found that the strains with accelerated aging share a specific provirus, Akv1, inherited from the AKR mouse progenitor of these strains. We found this virus to be highly expressed in thymus, spleen and brain of strains with accelerating aging. - Finally, we have developed several resources useful for mouse genomic analysis and mapping. We used these resources in a collaborative project with Dr. E. Rassart to identify a novel site of preferred integration for an oncogenic virus.