Pathogenesis of Familial Juvenile Polyposis

家族性幼年性息肉病的发病机制

• 批准号: 6542998
• 负责人: SHERRY C HUANG
• 金额: $ 12.11万
• 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/6542998
• 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（由申请人提供）：PTEN蛋白在多种器官的肿瘤中被认为是肿瘤抑制因子。 PTEN被认为是某些错构瘤性息肉病综合征的易感基因座，包括家族性幼年息肉病综合征（JPS）的病例。 了解JPS肿瘤发生的发病机制是重要的，因为JPS患者结直肠癌的终生风险显着增加。 我们的假设是，PTEN作为一个典型的肿瘤抑制基因在组织学良性表现错构瘤的患者与生殖系PTEN突变，其第二个等位基因是失活的错构瘤。 因为我们已经确定了息肉上皮部分内的微卫星不稳定性，第二个PTEN等位基因的失活可能来自DNA错配修复系统的一个组分的失活，该系统在DNA复制后识别并指导DNA的修复。 我们建议通过将野生型PTEN导入具有主要和次要错配修复蛋白破坏的错配修复缺陷细胞系来直接测试这一假设，以评估PTEN的失活。 对DNA修复作用和PTEN体细胞失活所涉及的分子事件的了解可能会增强我们对癌细胞发展的了解，并提供家族性错构瘤综合征癌症风险增加的机制。 本申请旨在进一步了解错构瘤性息肉综合征的发病机制，并为P.I.作为一个独立的医生科学家的发展。 私家侦探她致力于学术科学的职业生涯，并因其作为医生科学家的潜力而获得美国消化健康基金会研究员/教师过渡奖。 自从她完成儿科胃肠病学的临床培训以来，P.I.曾在约翰·M. Carethers，医学博士，胃肠道肿瘤领域的领导者。 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，错构瘤性息肉综合征的发病机制以及DNA错配修复系统的功能。 Carethers博士实验室正在进行的研究补充了拟议的研究，创造了一个刺激的环境，将提高P.I.的科学教育。 私家侦探也将由C博士共同指导理查德·博兰，加州大学圣地亚哥分校癌症中心副主任。 他在结肠癌遗传学方面很有声望，并将为申请人提供高级监督。 加州大学圣地亚哥分校的优秀科学资源，包括综合癌症中心提供的资源，将使P.I.发展合作，参加会议，探索新技术。