MECHANISMS OF PATHOGENESIS IN ATAXIA-TELANGIECTASIA

共济失调毛细血管扩张症的发病机制

• 批准号: 2756663
• 负责人: YANG XU
• 金额: $ 18.05万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2756663
• 关键词: T cell receptor; ataxia telangiectasia; autoimmune disorder; chromosome inversion; chromosome translocation; clinical research; cytogenetics; enzyme linked immunosorbent assay; fluorescent in situ hybridization; gene expression; genetic recombination; human subject; laboratory mouse; lymphoma; medical complication; molecular cloning; molecular oncology; neoplasm /cancer genetics; pathologic process; polymerase chain reaction; protooncogene; tissue /cell culture

Ataxia-telangiectasia (A-T) is an autosomally recessive human genetic disease characterized by pleiotropic defects, including greatly increased cancer risk, thymus hypoplasia and immunodeficiency. We have constructed a mouse model for A-T by disruption of the mouse ATM gene whose human counterpart is mutated in all A-T patients tested. The ATM- /- mice recapitulate most of the A-T defects, including greatly increased incidence of lymphoid tumors and immune defects. The overall objective of this proposal is to employ genetic and molecular methods to reveal the basis of the immune defects and high incidence of lymphoid tumors in the ATM-/- mice and affected patients. An increased frequency of chromosomal translocations and inversion involving the immunoglobulin or T cell receptor (TCR) loci, possibly as a result of illegitimate joining of these loci during V(D)J recombination, may cause the high incidence of lymphoid tumors in both A-T patients and ATM-/- mice through deregulated expression of protooncogenes. To test the involvement of the V(D)J recombination in the greatly increased incidence of thymic lymphomas in ATM-/-mice, the mouse ATM mutation will be introduced into the RAG-2-/-genetic background which is completely deficient in V(D)J recombination. If the V(D)J recombination is important for the lymphoid tumorigenesis in ATM-/- mice, this tumorigenesis should be suppressed or delayed in the ATM-/-RAG-2-/- genetic background. In addition, cytogenetic and molecular analysis of the lymphomas derived from ATM-/- mice will be performed to identify common chromosomal translocations involving known or potential oncogene loci in these lymphomas. The ATM-/- mice exhibit immune defects similar to those seen in A-T patients. To test whether the reduction of thymocytes in ATM-/- mice might be due to defects in cellular proliferation or disrupted V(D)J recombination or both, a functional TCRalphabeta chain will be introduced into the ATM-/- mice. These ATM- /-TCRalphabeta+ mice will also be used to study the basis of defective T-dependent immune responses in ATM-/- mice. ATM might play two potential roles in the V(D)J recombination: one role, similar to that of DNA-PK, involves the repair of DNA double-stranded breaks during V(D)J recombination; the other involves the cell-cycle regulation during V(D)J recombination. The lymphocytes derived from ATM-/- mice will be used to test these potential roles of ATM in the V(D)J recombination.

共济失调 - telangiectia（a-t）是一种常染色体隐性人类遗传 以多效性缺陷为特征的疾病，包括很大 癌症风险增加，胸腺发育不全和免疫缺陷。 我们有 通过破坏小鼠ATM基因构建了用于A-T的小鼠模型 在所有A-T患者中，其人类对应物被突变。 ATM- /-小鼠概括了大多数A-T缺陷，包括很大 淋巴样肿瘤和免疫缺陷的发生率增加。 总体 该建议的目的是采用遗传和分子方法 揭示免疫缺陷和高淋巴机的基础 ATM - / - 小鼠和受影响的患者中的肿瘤。 频率增加 涉及免疫球蛋白的染色体易位和反转 或T细胞受体（TCR）基因座，可能是由于非法而导致的 在V（d）J重组期间连接这些基因座，可能会导致高 A-T患者和ATM - / - 小鼠的淋巴样肿瘤的发病率 通过放松管制的原子基因表达。 测试 V（d）J重组参与大大增加 ATM - / - 小鼠中胸腺淋巴瘤的发生率，小鼠ATM突变将 被引入抹布-2 - / - 遗传背景，这完全是 缺乏V（d）J重组。 如果V（d）J重组是 对于ATM - / - 小鼠的淋巴肿瘤发生重要的重要 肿瘤发生应抑制或延迟在ATM - / - rag-2 - / - 遗传背景。 另外，细胞遗传学和分子分析 将执行源自ATM-/ - 小鼠的淋巴瘤以识别 常见的染色体易位，涉及已知或潜在癌细胞 这些淋巴瘤中的基因座。 ATM - / - 小鼠表现出免疫缺陷相似 对于在A-T患者中看到的人。 测试是否减少 ATM - / - 小鼠中的胸腺细胞可能是由于细胞中的缺陷 增殖或破坏V（d）J重组或两者兼具，功能性 Tcralphabeta链将引入ATM - / - 小鼠。 这些atm- /-tcralphabeta+小鼠也将用于研究缺陷的基础 TAMS - / - 小鼠中T依赖性免疫反应。 ATM可能会玩两个 V（d）J重组中的潜在作用：一个角色，类似 DNA-PK的涉及DNA双链休息的修复 V（d）J重组；另一个涉及在 V（d）J重组。 源自ATM-/ - 小鼠的淋巴细胞将是 用于在V（d）J重组中测试ATM的这些潜在作用。