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综合征，其特征是皮肤高斜形细胞膜和相关的小肠中息肉息肉，而小肠和结肠则会发生。这些患者还大大增加了出现多种不同肿瘤的风险，包括小肠，结肠癌，胰腺，胃，乳房，卵巢和睾丸的风险。 PJS是由编码丝氨酸苏氨酸激酶LKB1的基因中的种系突变引起的。最近的证据表明，LKB1基因是PJS患者的Hamartomas和腺癌中的肿瘤抑制剂。尽管该基因的功能尚不清楚，但Mehennni等人研究的LKB1突变。 （1998）当通过自身磷酸化测定时，所有这些都引起了激酶活性的损失。这是由于激酶活性损失而易于癌症的首个已知的蛋白激酶。该提案的总体目标是为PJ生成动物模型。这将使我们能够进行更多的长期研究，从而开发用于检测PJ患者的功能测定，开发通过PJS途径引起的癌症的早期检测策略以及PJ癌症的预防策略的发展。对所提出的动物模型的研究还将导致阐明LKB1的正常功能以及该基因破坏会增加与PJ相关癌症的风险的机制。将生成一个有条件的LKB1基因的敲除转基因小鼠系。将检查由小鼠LKB1等位基因之一的破坏产生的表型。 Mot人类具有PJ的lkb1有一个无效等位基因，第二等位基因在Hamartomas和腺癌中丢失或突变。假设一个无效等位基因的小鼠的表型将与PJ相似。将确定由LKB1基因的纯合破坏产生的表型。如果纯合子敲除小鼠不可行，则会产生组织特异性的条件敲除小鼠，以允许LKB1基因在胃肠道组织（包括胰腺）中的影响。如果由于执行上述目的而在小鼠中未观察到腺癌，则携带LKB1无效等位基因的生存小鼠将与携带p53无效等位基因的小鼠交叉。将检查这些小鼠的表型，以确定敲除LKB1是否会加速小鼠的肿瘤发生途径。由于已知p53中的突变经常发生在PJS患者的腺癌中，因此p53突变和LKB1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。