MOUSE MODEL FOR BLOOM SYNDROME & TUMOR SUPPRESSOR GENES

布卢姆综合症小鼠模型

• 批准号: 6378195
• 负责人: GUANGBIN LUO
• 金额: $ 13.6万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-21 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6378195
• 关键词: Bloom syndrome; disease /disorder model; gene mutation; gene targeting; genetic crossing over; genetic recombination; genetic susceptibility; genetically modified animals; helicase; laboratory mouse; loss of heterozygosity; model design /development; neoplasm /cancer genetics; tumor suppressor genes

DESCRIPTION (Applicant's Description): The long-term objective of this grant is to study the underlying mechanisms that govern somatic recombination and somatic loss of heterozygosity (LOH) during cancer development and to develop mouse models with increased rates of somatic LOH as tools to identify novel tumor suppressor genes. Somatic LOH plays an important role in cancer development. It is largely responsible for the second event that is required for the complete loss of function of a tumor suppressor gene. Thus the understanding of these mechanisms will be important for the advancement of our knowledge on the initiation and/or progression of cancer and hence may lead to better diagnosis, prevention and treatments of this disease. In mammalian cells, there exist two major pathways that can lead to LOH: chromosome mis- segregation, and recombination-based (segmental) LOH, with the segmental type of LOH being the predominant type in human cancer. The human Bloom syndrome provides a unique model to study this important process. Bloom syndrome is a cancer-prone disorder due to loss of function mutations in a gene encoding a RecQ DNA helicase. Studies in E. coli and in yeast suggest that the RecQ helicase is an antagonist of recombination. Both Bloom syndrome patients and the corresponding yeast mutants display a hyper-recombination phenotype. It is therefore hypothesized that Bloom syndrome patients are predisposed to cancer due to an elevated segmental LOH process that accelerates the uncovering of phenotypic effects of otherwise silent single mutations in tumor suppressor genes. in addition, it has been reported very recently that the Rothmund- Thomson syndrome, another cancer prone syndrome, is caused by mutations in RecQ4, another gene coding for a RecQ DNA helicase. Thus, mouse models of these syndromes should provide excellent tools to study segmental LOH and may also be useful for gene identification in a genetic screen. The specific aims of this grant are: to generate mouse models of the human Bloom syndrome and Rothmund-Thomson syndrome; to study effects of mutations in Blm and RecQ4 on somatic recombination and LOH; to examine the effects of mutations in Blm and RecQ4 on tumor susceptibility in mice; and to evaluate the usefulness of these mouse models as tools to increase the ease of identifying novel tumor suppressor genes in the context of somatic insertion- tagged mutagenesis.

描述(申请者的描述)：这项资助的长期目标 是研究支配体细胞重组和 肿瘤发生发展过程中的体细胞杂合性丢失(LOH) 体细胞杂合性缺失发生率增加的小鼠模型作为识别新基因的工具 肿瘤抑制基因。 体细胞杂合性缺失在肿瘤的发生发展中起着重要作用。它在很大程度上 对完全损失所需的第二个事件负责 肿瘤抑制基因的功能。因此，对这些的理解 机制对于增进我们对 癌症的发生和/或进展，因此可能导致更好的 该病的诊断、预防和治疗。在哺乳动物细胞中， 有两条主要途径可导致杂合性丢失：染色体错位 分离和基于重组的(节段性)LOH，具有节段型 杂合性缺失是人类癌症的主要类型。人类布卢姆综合征 为研究这一重要过程提供了独特的模型。布鲁姆综合征是一种 由于编码A基因的功能突变而导致的癌症易感性疾病 RECQ DNA解旋酶。在大肠杆菌和酵母中的研究表明，RecQ 解旋酶是重组的拮抗剂。布卢姆综合征患者和 相应的酵母突变体表现出超重组表型。它是 因此假设布卢姆综合征患者易患癌症 由于升高的节段性LOH过程加速了对 肿瘤抑制基因中沉默的单个突变的表型效应 基因。此外，最近有报道称，罗斯蒙德- 汤姆森综合征是另一种易患癌症的综合征，由基因突变引起 RecQ4，另一个编码RecQ DNA解旋酶的基因。因此，小鼠模型 这些综合征应该为研究节段性LOH提供了很好的工具，并可能 对于基因筛查中的基因识别也是有用的。 这笔赠款的具体目标是：制造人类的老鼠模型 Bloom综合征和Rothmund-Thomson综合征；研究突变对 BLM和RecQ4对体细胞重组和杂合性丢失的影响 BLM和RecQ4基因突变对小鼠肿瘤易感性的影响 这些鼠标模型作为工具的有用性增加了 在体细胞插入的背景下识别新的肿瘤抑制基因- 标记突变。