PATHOGENETIC MECHANISMS IN FELINE LEUKEMIA

猫白血病的致病机制

• 批准号: 2094297
• 负责人: PRADIP ROY-BURMAN
• 金额: $ 23.47万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-01-01 至 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2094297
• 关键词: alleles; cats; feline leukemia /sarcoma virus; genetic recombination; host organism interaction; immunofluorescence technique; immunosuppression; lymphoma; newborn animals; polymerase chain reaction; protooncogene; provirus; viral leukemia; virus genetics

The long-term goal of this program is to identify the multiple events that interplay in the pathogenesis of lymphoid malignancies in the domestic cat. This outbred species has the highest incidence of leukemia-lymphoma of any animal, and horizontal infection by the naturally occurring feline leukemia virus is related to its increased susceptibility to leukemogenesis. Events that occur during the prolonged viremic period are mostly unknown, except that infected cats become immunosuppressed and that in many thymic lymphomas the c-myc proto-oncogene is either transduced or insertionally activated. While the proximal leukomogens for the disease are unknown, there is evidence for homologous recombination between viral and endogenous cellular retrovirus elements. The characterization of these endogenous sequences of the domestic cat genome and isolation of two commonly occurring alleles of the feline c-myc gene provide the basis for the present study. There is evidence that one type of homozygosity at the c- myc locus is rare, while the other type of homozygosity that commonly occurs in cats may be associated with increased frequency of lymphomas. The specific aims are as follows: (1) examine the role of specific viral subgroups and recombination between endogenous and exogenous retroviral genes in dictating in vivo tissue tropism and disease specificities; (2) examine the impairment of the host's immune response by the variants to identify the viral determinants for immunosuppression; (3) determine genetic properties of the isolated c-myc alleles in terms of functional and structural differences and confirm that the observations extend generally to the detection of similar structural changes in cat genomic DNAs; and (4) identify the proximal agents that are involved in the rearrangement of the c-myc gene and determine if there is allele specificity for activation and consequent biological activity. The model system offers the opportunity of examining the interaction between exogenous and endogenous retrovirus genes and between provirus elements and a widely implicated proto-oncogene with biologically significant allelic variations in the development of lymphoid tumors in an outbred animal species.

该计划的长期目标是确定多个事件， 在家猫淋巴恶性肿瘤发病机制中的相互作用。 这种远交种的白血病淋巴瘤的发病率最高的任何 动物，以及自然发生的猫白血病的水平感染 病毒与其对白血病发生的易感性增加有关。 事件 在长期病毒血症期间发生的疾病大多是未知的，除了 受感染的猫会受到免疫抑制， c-myc原癌基因是转导的或插入的 激活 虽然这种疾病的近端白血病原是未知的， 有证据表明病毒和内源性病毒之间存在同源重组， 细胞逆转录病毒元件。 这些内源性的特征 家猫基因组序列和两种常见的 猫c-myc基因的等位基因的出现提供了基础 本研究。 有证据表明，一种类型的纯合子在c- myc基因座是罕见的，而其他类型的纯合性，通常 发生在猫可能与淋巴瘤的频率增加。 具体目的如下：（1）研究特定病毒在 内源性和外源性逆转录病毒之间的亚群和重组 决定体内组织嗜性和疾病特异性的基因;（2） 检查变异体对宿主免疫反应的损害， 确定免疫抑制的病毒决定因素;（3）确定 分离的c-myc等位基因在功能和 结构差异，并确认观察结果普遍延伸 在猫基因组DNA中检测类似的结构变化;和（4） 识别参与重组的近端代理， c-myc基因，并确定是否存在激活的等位基因特异性， 随之而来的生物活动。 模型系统提供了以下机会： 检测外源和内源逆转录病毒基因之间的相互作用 以及前病毒元件和一个广泛相关的原癌基因之间的关系， 在淋巴细胞发育中具有生物学意义的等位基因变异 远系繁殖动物的肿瘤