MOUSE MODEL FOR THE PEUTZ JEGHERS SYNDROME

黑息综合症小鼠模型

• 批准号: 6489438
• 负责人: MARSHA L. FRAZIER
• 金额: $ 7.5万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-03 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6489438
• 关键词: adenocarcinoma; colon disorder; disease /disorder model; gastrointestinal neoplasms; gene mutation; genetically modified animals; laboratory mouse; model design /development; neoplasm /cancer genetics; protein kinase; syndrome; tumor suppressor genes

Peutz-Jeghers syndrome (PJS) is a unique autosomal dominant syndrome characterized by cutaneous hypermelanocytic macules and associated hamartomatous polyp develop in the small bowel and colon. These patients also have a dramatically increased risk for development of a variety of different neoplasias including those of the small bowel, colon, pancreas, stomach, breast, ovary and testicle. PJS is caused by germline mutations in the gene encoding the serine threonine kinase LKB1. Recent evidence that the LKB1 gene is a tumor suppressor in hamartomas and adenocarcinomas from PJS patients. Although the function of the gene is not known, the LKB1 mutations studied by Mehennni et al. (1998) all caused a loss of kinase activity when assayed by auto-phosphorylation. This is the first known protein kinase that predisposes to cancer because of a loss of the kinase activity. The overall goal of the proposal is to generate an animal model for PJS. This will allow us to conduct more long-term studies leading to the development of functional assays for the detection of patients with PJS, the development of early detection strategies for cancer arising via the PJS pathway, and the development of preventive strategies for PJS cancers. Studies of the proposed animal model will also lead to the elucidation of the normal function of LKB1 and the mechanism by which disruption of this gene increases risk for PJS associated cancers. A conditional knock-out transgene mouse line for the lkb1 gene will be generated. The phenotype resulting from disruption of one of the mouse LKB1 alleles will be examined. Mot humans with PJS have one null allele for LKB1, the second allele is lost or mutated in hamartomas and adenocarcinomas. It is hypothesized that mice with one null allele will have a phenotype similar to the PJS. The phenotype resulting from the homozygous disruption of the lkb1 gene will be determined. If homozygous knock-out mice are not viable, tissue-specific conditional knock-out mice will e created to allow the effects of the lkb1 gene in the gastrointestinal tissues (including pancreas) to be studied. If adenocarcinomas are not observed in mice as a result of carrying out the aims described above, viable mice carrying lkb1 null alleles will be crossed with mice carrying a p53 null allele. The phenotype of these mice will be examined to determine if knocking out lkb1 accelerates the pathway for tumorigenesis in the mice. Because mutations in p53 are known to occur frequently in adenocarcinomas of PJS patients, the combination of the p53 mutation and the lkb1 null allele would provide two hints in the PJS pathway of tumorigenesis.

Peutz-Jeghers综合征(PJS)是一种独特的常染色体显性遗传性综合征，以皮肤黑素细胞增多的斑点和伴发于小肠和结肠的错构瘤性息肉为特征。这些患者患各种不同肿瘤的风险也显著增加，包括小肠、结肠、胰腺、胃、乳腺、卵巢和睾丸的肿瘤。PJS是由编码丝氨酸苏氨酸激酶LKB1基因的胚系突变引起的。最近的证据表明LKB1基因在PJS患者的错构瘤和腺癌中是一种肿瘤抑制因子。虽然该基因的功能尚不清楚，但Mehennni等人研究的LKB1突变。(1998)，当用自动磷酸化检测时，所有这些都导致了激酶活性的丧失。这是第一个已知的蛋白激酶，由于该激酶活性的丧失而易患癌症。该提案的总体目标是为PJS生成一个动物模型。这将使我们能够进行更多的长期研究，从而开发检测PJS患者的功能分析方法，开发通过PJS途径产生的癌症的早期检测策略，以及开发PJS癌症的预防策略。对所提出的动物模型的研究也将有助于阐明LKB1的正常功能以及该基因中断增加PJS相关癌症风险的机制。将产生一个有条件地敲除lkb1基因的转基因小鼠系。我们将检查由于其中一个小鼠LKB1等位基因的破坏而导致的表型。大多数PJS患者有一个LKB1零等位基因，第二个等位基因在错构瘤和腺癌中丢失或突变。据推测，带有一个零等位基因的小鼠将具有类似于PJS的表型。将确定由于1kb1基因纯合破坏而导致的表型。如果纯合子基因敲除小鼠不能存活，将创建组织特异性条件性基因敲除小鼠，以允许研究胃肠道组织(包括胰腺)中lkb1基因的影响。如果由于上述目的的实现，没有在小鼠身上观察到腺癌，携带Lkb1零等位基因的存活小鼠将与携带P53零等位基因的小鼠杂交。这些小鼠的表型将被检测，以确定敲除lkb1是否加速了小鼠肿瘤形成的途径。由于已知PJS患者的腺癌中经常发生P53突变，P53突变和Lkb1缺失等位基因的结合将在PJS的肿瘤发生途径中提供两个线索。