Humoral immunodeficiency in cancer-prone SENCAR mice

易患癌症的 SENCAR 小鼠的体液免疫缺陷

• 批准号: 6327444
• 负责人: Andrea Bottaro
• 金额: $ 34.88万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2003-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6327444
• 关键词: DNA repair; cancer risk; gene rearrangement; genetic susceptibility; humoral immunity; immunodeficiency; immunoglobulin genes; laboratory mouse; linkage mapping; molecular cloning

DESCRIPTION (Provided by Applicant): The study of the well-known association of immunodeficiency diseases and cancer susceptibility has recently shifted from clinical and epidemiological correlation into the molecular and cellular biology fields. Analysis of human patients and mouse models has shown that immunodeficiency and increased risk of cancer can in some cases be the direct effects of the same underlying mutation in one of the factors involved in antigen receptor gene rearrangement and DNA repair/cell cycle control, such as the cell cycle checkpoint regulator, atm (which is mutated in ataxia telangiectasia) and the Ku70 DNA repair factor. In addition, an association between impaired immunoglobulin G (IgG) production and increased cancer susceptibility has been found in mismatch repair-deficient mice. Together with other findings, these latter observations have indicated an involvement of DNA repair pathways in immunoglobulin class switch recombination. We have identified a new type of humoral immunodeficiency in SENCAR/A mice, a widely studied model of genetic susceptibility to carcinogenesis. This novel immune phenotype includes low serum IgG3 levels, absence of IgG responses to T-independent antigens, and low IgG2b switching in vitro. We have shown that the immunodeficiency is inherited as a co-dominant, monogenic trait, and that it is absent in a SENCAR-related strain that has also lost one of the cancer susceptibility loci. This phenotype is unique, although it resembles, in some aspects, that of DNA mismatch repair mutant mice and some human immunodeficiency syndromes. We propose to test the hypothesis that the novel immunodeficiency and the cancer susceptibility phenotypes of SENCAR/A mice are genetically and functionally linked, possibly due to a defect in DNA repair. We will characterize the SENCAR/A defect at the molecular level by establishing its impact on the mechanism of class switch recombination, and we will apply a genetic assay to unveil underlying DNA repair deficiencies. Moreover, we will use linkage analysis and positional cloning techniques to map and identify the affected gene, and to establish its potential involvement in cancer susceptibility.

描述（由申请人提供）：研究众所周知的 免疫缺陷疾病和癌症易感性最近从 临床和流行病学相关性的分子和细胞 生物领域。对人类患者和小鼠模型的分析表明， 免疫缺陷和癌症风险增加在某些情况下可能是直接的 在参与的一个因素中的相同潜在突变的影响 抗原受体基因重排和DNA修复/细胞周期控制，如 细胞周期检查点调节因子ATM（其在共济失调中突变 毛细血管扩张）和Ku 70 DNA修复因子。此外，一个协会 免疫球蛋白G（IgG）产生受损和癌症增加之间的关系 在错配修复缺陷小鼠中发现了易感性。连同 其他的发现，这些后面的观察表明，DNA参与 免疫球蛋白类别转换重组中的修复途径。 我们在SENCAR/A小鼠中发现了一种新型的体液免疫缺陷， 被广泛研究的致癌遗传易感性模型。这本小说 免疫表型包括低血清IgG 3水平，缺乏IgG应答， T-非依赖性抗原和体外低IgG 2b转换。我们已经证明 免疫缺陷作为共显性单基因性状遗传， 它在SENCAR相关菌株中不存在，该菌株也失去了其中一种癌症 易感基因座这种表型是独特的，虽然它类似，在一些 DNA错配修复突变小鼠和一些人的DNA错配修复突变小鼠和一些人的DNA错配修复突变小鼠和一些人的DNA错配修复突变小鼠。 免疫缺陷综合征 我们建议测试的假设，新的免疫缺陷和 SENCAR/A小鼠的癌症易感性表型是遗传的， 在功能上相连，可能是由于DNA修复缺陷。我们将 在分子水平上表征SENCAR/A缺陷 影响类切换重组的机制，我们将应用一个 基因检测揭示潜在的DNA修复缺陷。而且还要 利用连锁分析和定位克隆技术， 受影响的基因，并确定其在癌症中的潜在参与 易感性