MOUSE MODEL FOR BLOOM SYNDROME & TUMOR SUPPRESSOR GENES

描述（申请人的描述）：本补助金的长期目标 是研究控制体细胞重组的潜在机制， 体细胞杂合性丢失（洛）在癌症发展过程中， 体细胞洛缺失率增加的小鼠模型作为鉴定新的 肿瘤抑制基因 体细胞洛缺失在肿瘤发生发展中起重要作用。大程度上是 第二种情况是完全丧失 肿瘤抑制基因的功能。 因此，理解这些 机制将是重要的进步，我们的知识， 癌症的开始和/或进展，因此可能导致更好的 诊断，预防和治疗这种疾病。在哺乳动物细胞中， 存在两种可导致洛缺失的主要途径：染色体错配- 分离，和重组为基础的（节段性）洛缺失，与节段性 洛缺失是人类癌症的主要类型。人类布鲁姆综合症 为研究这一重要过程提供了一个独特的模型。布鲁姆综合症是一种 由于编码A的基因功能丧失突变而导致的癌症易感疾病 RecQ DNA解旋酶。 在E. 大肠杆菌和酵母中的RecQ表明， 解旋酶是重组拮抗剂。布鲁姆综合征患者和 相应的酵母突变体显示出超重组表型。是 因此，我假设布卢姆综合征患者易患癌症， 由于升高的节段性洛过程加速了 肿瘤抑制基因沉默单突变的表型效应 基因. 此外，最近有报道称，罗斯蒙特- 汤姆森综合征，另一种癌症倾向综合征，是由基因突变引起的。 RecQ 4，另一个编码RecQ DNA解旋酶的基因。因此， 这些综合征为研究节段性洛缺失提供了极好的工具， 也可用于遗传筛选中的基因鉴定。 这项资助的具体目标是： Bloom综合征和Rothmund-Thomson综合征;研究基因突变对 Blm和RecQ 4对体细胞重组和洛缺失的影响; Blm和RecQ 4突变对小鼠肿瘤易感性的影响;并评估 这些小鼠模型作为工具的有用性， 在体细胞插入的背景下鉴定新的肿瘤抑制基因- 标记诱变

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.