MOUSE MODEL FOR THE PEUTZ JEGHERS SYNDROME

黑息综合症小鼠模型

• 批准号: 6292089
• 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 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6292089
• 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综合征，其特征是在小肠和结肠发生皮肤高黑素细胞斑和相关的错构瘤性息肉。这些患者还具有发生各种不同肿瘤的显著增加的风险，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LKB 1的基因中的种系突变引起的。最近的证据表明LKB 1基因是PJS患者错构瘤和腺癌的肿瘤抑制因子。尽管该基因的功能尚不清楚，但Mehennni等人（1998）研究的LKB 1突变在通过自磷酸化测定时均导致激酶活性丧失。这是第一个已知的蛋白激酶，易患癌症，因为激酶活性的损失。该提案的总体目标是为PJS生成动物模型。这将使我们能够进行更长期的研究，从而开发用于检测PJS患者的功能检测方法，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LKB 1的正常功能以及该基因的破坏增加PJS相关癌症风险的机制。将产生lkb 1基因的条件性敲除转基因小鼠系。将检查由小鼠LKB 1等位基因之一破坏产生的表型。大多数患有PJS的人都有一个LKB 1的无效等位基因，第二个等位基因在错构瘤和腺癌中丢失或突变。假设具有一个无效等位基因的小鼠将具有与PJS相似的表型。将确定lkb 1基因纯合破坏产生的表型。如果纯合基因敲除小鼠不能存活，将建立组织特异性条件性基因敲除小鼠，以研究lkb 1基因在胃肠道组织（包括胰腺）中的作用。如果由于实施上述目的而在小鼠中未观察到腺癌，则将携带lkb 1无效等位基因的存活小鼠与携带p53无效等位基因的小鼠杂交。将检查这些小鼠的表型以确定敲除lkb 1是否加速小鼠中的肿瘤发生途径。因为已知p53突变经常发生在PJS患者的腺癌中，所以p53突变和lkb 1无效等位基因的组合将在肿瘤发生的PJS途径中提供两个提示。