MHC Loci in the Control of Marek's Lymphoma

MHC 位点控制马立克氏淋巴瘤

• 批准号: 6909121
• 负责人: MARCIA M MILLER
• 金额: $ 15.48万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6909121
• 关键词: Herpesviridae; Marek' s disease; RNase protection assay; alleles; chickens; disease /disorder model; genetic recombination; genotype; immunogenetics; inbreeding; major histocompatibility complex; microorganism immunology; nucleic acid sequence; polymerase chain reaction; tumor suppressor genes

DESCRIPTION (provided by applicant): Oncogenic herpes viruses drive most cancers associated with HIV infection and other immunosuppressed conditions. The close association between immunity and tumor growth in these cancers is obvious. Relief of immunosuppression can bring cancer remission. Over time complex interactions have evolved between oncogenic virus, tumor and vertebrate host. The Marek's disease (MD) virus in the chicken provides useful model for learning more about the role of vertebrate genetics in controlling tumor growth caused by herpes virus transformation. Particular major histocompatibility complex (MHC) haplotypes in the chicken have strikingly strong roles in suppressing the growth of MD lymphomas, while other MHC haplotypes provide moderate or no protection. Two ostensibly identical recombinant MHC haplotypes were shown in earlier studies to differ in response to MD tumors. In preliminary work we have demonstrated that, although identical at class I, class II and a cluster of BG loci, the two recombinant haplotypes differ in crossover breakpoints within a restricted region in the vicinity of a distinctive BG locus that has intriguing features and is likely involved in signaling. In addition to the unusual BG locus there is a putative NK-cell receptor gene posited as important in controlling tumor growth (surrounded by long-inverted repeats that are typical of DNA predisposed to instability and increased homologous recombination in adjacent regions). We seek to 1) confirm the difference between the two recombinant haplotypes, BR2 and BR4 in response to challenge with MD virus and extend the test to include a third closely related recombinant haplotype BR3 using fully congenic strains now available in additional MDV challenge trials; 2) define the allelic differences at the candidate loci in BR2-BR4 recombinant haplotypes and haplotypes conferring high resistance and high susceptibility to MD tumors by resequencing the interval surrounding the crossover breakpoints; and 3) study the constitutive expression of candidate loci in organs associated with MDV infection and profile changes which occur in these and other loci during the course of viral infection and tumor formation in birds that bear the different MHC haplotypes and differ in tumor growth following infection.

描述（由申请人提供）：致癌疱疹病毒推动了大多数与HIV感染和其他免疫抑制条件相关的癌症。这些癌症中免疫与肿瘤生长之间的密切关联是显而易见的。免疫抑制的缓解会带来癌症的缓解。随着时间的流逝，复杂的相互作用在致癌病毒，肿瘤和脊椎动物宿主之间发展。鸡肉中的Marek病（MD）病毒提供了有用的模型，以更多地了解脊椎动物遗传学在控制疱疹病毒转化引起的肿瘤生长中的作用。鸡肉中特定的主要组织相容性复合物（MHC）单倍型在抑制MD淋巴瘤的生长方面具有极大的作用，而其他MHC单倍型可提供中等或没有保护。在早期的研究中显示了两种表面上相同的重组MHC单倍型，这些重组对MD肿瘤的反应有所不同。在初步工作中，我们已经证明，尽管在I类，II类和BG基因群的I类中相同，但两种重组单倍型在一个有限的BG基因座附近的跨界区域内有不同，该区域具有独特的BG基因座，具有吸引人的特征，可能涉及信号传导。除了不寻常的BG基因座外，还有一个假定的NK细胞受体基因对控制肿瘤生长至关重要（周围环绕着较长的重复序列，这些重复序列是典型的DNA，易于不稳定性和相邻区域的同源重组增加）。我们寻求1）确认两种重组单倍型，BR2和BR4之间的差异，以响应MD病毒的挑战，并将测试扩展到包括第三次紧密相关的重组单倍型BR3，使用现在在其他MDV挑战试验中可用的完全先天性菌株； 2）在BR2-BR4重组单倍型和单倍型中定义候选基因座的等位基因差异，通过重塑围绕交叉断点的间隔来赋予高电阻和对MD肿瘤的高敏感性； 3）研究在病毒感染和其他基因座中发生的与MDV感染和特征变化相关的器官中的候选基因座的本构表达，在病毒感染和鸟类形成过程中，在鸟类中具有不同的MHC单倍型，并且在感染后肿瘤生长不同。

项目成果

Contribution of mutation, recombination, and gene conversion to chicken MHC-B haplotype diversity.

• DOI: 10.4049/jimmunol.181.5.3393
• 发表时间: 2008-09-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Hosomichi K;Miller MM;Goto RM;Wang Y;Suzuki S;Kulski JK;Nishibori M;Inoko H;Hanzawa K;Shiina T
• 通讯作者: Shiina T