The Molecular Basis of Rothmund-Thomson Syndrome

罗斯蒙德-汤姆森综合征的分子基础

• 批准号: 6704756
• 负责人: Lisa L Wang
• 金额: $ 12.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6704756
• 关键词: DNA replication; cancer risk; cataract; chromosome disorders; congenital skin disorder; diagnosis design /evaluation; disease /disorder etiology; family genetics; gene mutation; genetic disorder diagnosis; genetic screening; genetic susceptibility; genotype; helicase; human subject; molecular pathology; neoplasm /cancer genetics; orphan disease /drug; osteosarcoma; pathologic process; patient oriented research; phenotype; postdoctoral investigator; skeletal disorder

DESCRIPTION (provided by applicant): Rothmund-Thomson syndrome (RTS) is a rare inherited, chromosomal instability syndrome belonging to the RecQ family of helicase disorders, and is characterized by skin rash, skeletal abnormalities, small stature, juvenile cataracts, and a significant cancer predisposition, particularly for osteosarcoma. The hypothesis of this study is that detailed study of rare cancer predisposition syndromes, such as RTS, will provide significant new insights into the molecular basis of genomic stability and the etiology of both inherited and sporadic cancers. The broad objectives of this project are to understand the molecular, clinical, and cellular features of RTS. The clinical findings will have implications in many areas of pediatrics, including genetics, dermatology, ophthalmology, and oncology. The molecular and cellular findings will contribute to understanding of other related chromosome instability syndromes and may lead to an assay for the diagnosis of RTS. The first specific aim involves comprehensive molecular analysis coupled with detailed clinical description of RTS patients enrolled in an IRB-approved General Clinical Research Center study at Baylor College of Medicine (BCM). Screening for mutations in the RECQL4 gene will be performed by sequencing of genomic DNA and DHPLC screening of cDNA in probands. Genotype/phenotype associations will be generated from clinical and molecular data. The second specific aim will involve investigation of the presently unknown cellular defects in RTS. The response of RTS cells to a variety of agents that cause DNA damage or replication blocks will be analyzed with respect to sensitivity and cell cycle progression. Understanding the basic helicase defect through study of paradigm disorders such as RTS may provide insight into mechanisms of cancer pathogenesis and may have important clinical implications in the management of these patients. This Mentored Clinical Scientist Development Award would serve as a vehicle to allow the candidate to accomplish her immediate training goals in a mentored scientific environment, and to reach the candidate's long-term career goals as a physician-scientist in pediatric oncology. The mentor and the superb facilities and resources at BCM will provide the ideal environment for the candidate during the period covered by the K08 award. This experience will provide the foundation upon which to build the candidate's career as an independent investigator.

描述（由申请人提供）： Rothmund-Thomson 综合征 (RTS) 是一种 属于 RecQ 家族的罕见遗传性染色体不稳定综合征 解旋酶疾病，其特征是皮疹、骨骼 异常、身材矮小、青少年白内障和重大癌症 易感性，特别是骨肉瘤。 本研究的假设 是对罕见癌症易感综合征（例如 RTS）的详细研究， 将为基因组的分子基础提供重要的新见解 遗传性和散发性癌症的稳定性和病因学。 广义的 该项目的目标是了解分子、临床和 RTS 的蜂窝特征。 临床研究结果将产生影响 儿科的许多领域，包括遗传学、皮肤病学、眼科等 肿瘤学。 分子和细胞研究结果将有助于 了解其他相关的染色体不稳定综合征，并可能导致 用于诊断 RTS 的测定。 第一个具体目标涉及 全面的分子分析加上详细的临床描述 RTS 患者加入 IRB 批准的普通临床研究中心 在贝勒医学院（BCM）学习。 筛选突变 RECQL4基因将通过基因组DNA测序和DHPLC筛选进行 先证者的 cDNA。 基因型/表型关联将产生于 clinical and molecular data. 第二个具体目标将涉及 RTS 中目前未知的细胞缺陷的研究。 回应 RTS 细胞对多种导致 DNA 损伤或复制的物质的影响 将根据敏感性和细胞周期对模块进行分析 进展。 通过研究了解解旋酶的基本缺陷 RTS 等范式障碍可能有助于深入了解癌症机制 发病机制，可能对治疗具有重要的临床意义 这些病人。 该指导临床科学家发展奖将 作为让候选人完成即时培训的工具 在有指导的科学环境中实现目标，并达到候选人的目标 作为儿科肿瘤学医师科学家的长期职业目标。 这 BCM 的导师以及一流的设施和资源将为您提供理想的选择 K08 奖项涵盖期间为候选人提供的环境。 这些经验将为建立 候选人作为独立调查员的职业生涯。