Pathogenesis of Familial Juvenile Polyposis

家族性幼年性息肉病的发病机制

• 批准号: 7112426
• 负责人: SHERRY C HUANG
• 金额: $ 12.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7112426
• 关键词: DNA repair; DNA replication; alleles; cancer risk; carcinogenesis; cell line; clinical research; colorectal neoplasms; gene mutation; human subject; immunocytochemistry; neoplastic growth; nucleic acid sequence; transfection; tumor suppressor genes; tumor suppressor proteins

DESCRIPTION (provided by applicant): The PTEN protein has been implicated as a tumor suppressor in neoplasms of various organs. PTEN is recognized as the susceptibility locus for some hamartomatous polyposis syndromes including cases of familial Juvenile Polyposis Syndrome (JPS). Understanding the pathogenesis of tumorigenesis in JPS is important because of the significant increased lifetime risk for colorectal cancer in JPS patients. Our hypothesis is that PTEN acts as a classic tumor suppressor gene in the histologically benign-appearing hamartomas from patients with germ-line PTEN mutations in that its second allele is inactivated in hamartomas. Because we have identified microsatellite instability within the epithelial portion of the polyps, inactivation of the second PTEN allele might be from inactivation of a component of the DNA mismatch repair system, a system which recognizes and directs repair of DNA after its replication. We propose to directly test this hypothesis by transfecting wild-type PTEN into mismatch repair-defective cell lines with major and minor mismatch repair protein disruptions to assess for inactivation of PTEN. An understanding of the molecular events involved in the role of DNA repair and the somatic inactivation of PTEN may enhance our understanding of the development of the cancer cell, and provide a mechanism for the increased cancer risk in familial hamartomatous syndromes. This application is designed to pursue advances in our understanding of the pathogenesis of hamartomatous polyposis syndromes as well as provide a foundation for the P.I.'s development as an independent physician scientist. The P.I. is dedicated to a career in academic science, and was recognized for her potential as a physician scientist by receiving the American Digestive Health Foundation Fellow/Faculty Transition Award. Since the completion of her clinical training in Pediatric Gastroenterology, the P.I. has engaged in basic science research in the laboratories of John M. Carethers, M.D., a leader in the field of gastrointestinal oncology. Dr. Carethers' research focuses on mechanisms of tumorigenesis, including the biology and genetics of colon cancer, the pathogenesis of hamartomatous polyposis syndromes, and function of the DNA mismatch repair system. Ongoing studies in Dr. Carethers' laboratory complement the proposed studies, creating a stimulating setting that will enhance the P.I.'s scientific education. The P.I. will also be co-mentored by Dr. C. Richard Boland, Associate Director of the Cancer Center at UCSD. He is well regarded in colon cancer genetics and will provide senior supervision to the applicant. Outstanding scientific resources at the University of California, San Diego, including those offered by the Comprehensive Cancer Center, will allow the P.I. to develop collaborations, participate in conferences, and to explore new technology.

描述(申请人提供)：PTEN蛋白被认为是一种肿瘤抑制因子，与多种器官的肿瘤有关。PTEN被认为是一些错构瘤性息肉病综合征的易感基因，包括家族性青少年息肉综合征(JPS)。了解JPS的肿瘤发生机制是很重要的，因为JPS患者的结直肠癌的终生风险显著增加。我们的假设是，PTEN在组织学上良性的错构瘤中扮演着经典的肿瘤抑制基因的角色，因为它的第二个等位基因在错构瘤中是失活的。由于我们已经在息肉的上皮部分发现了微卫星的不稳定性，第二个PTEN等位基因的失活可能是由于DNA错配修复系统的一个组件的失活，该系统识别并指导DNA复制后的修复。我们建议通过将野生型PTEN导入具有重大和微小错配修复蛋白中断的错配修复缺陷细胞系来直接检验这一假设，以评估PTEN的失活。了解参与DNA修复和PTEN的体细胞失活的分子事件可能会增强我们对癌细胞发展的理解，并为家族性错构瘤综合征增加癌症风险提供机制。这项申请旨在促进我们对错构瘤性息肉病综合征发病机制的理解，并为P.I.S作为独立内科科学家的发展奠定基础。 这位P.I.致力于学术科学的事业，并因其作为内科科学家的潜力而受到认可，她获得了美国消化健康基金会院士/教师过渡奖。自完成儿科胃肠病学临床培训以来，P.I.一直在胃肠道肿瘤学领域的领先者John M.Carethers，M.D.的实验室从事基础科学研究。Carethers博士的研究重点是肿瘤发生的机制，包括结肠癌的生物学和遗传学，错构瘤息肉综合征的发病机制，以及DNA错配修复系统的功能。卡雷瑟斯实验室正在进行的研究是对拟议研究的补充，将创造一个激动人心的环境，将加强P.I.S的科学教育。P.I.还将由加州大学圣地亚哥分校癌症中心副主任C.Richard Boland博士共同指导。博兰博士在结肠癌遗传学方面享有很高的声誉，将为申请者提供高级监督。加州大学圣地亚哥分校(University of California，San Diego)出色的科学资源，包括综合癌症中心提供的资源，将使P.I.能够开展合作、参加会议和探索新技术。