GENETIC DISSECTION OF A BONE DYSPLASIA/CANCER SYNDROME

骨发育不良/癌症综合征的基因解剖

• 批准号: 6520606
• 负责人: JOHN A MARTIGNETTI
• 金额: $ 8.53万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-05 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6520606
• 关键词: artificial chromosomes; autosomal dominant trait; bone disorder; bone neoplasms; cell line; clinical research; cyclin dependent kinase; disease /disorder etiology; family genetics; gene expression; genetic markers; human genetic material tag; human subject; linkage mapping; loss of heterozygosity; neoplasm /cancer genetics; sarcoma; southern blotting; syndrome; transcription factor

This application is designed to provide Dr. John Martignetti a program of mentored laboratory research to facilitate his development as an independent physician-scientist. After completing his pediatric genetics fellowship, he will become an Assistant Professor of Human Genetics and Pediatrics at the Mount Sinai School of Medicine on July 1, 1998. He recently diagnosed a family with a rare inherited skeletal dysplasia/cancer syndrome, hereditary bone dysplasia (HBD) with malignant change , a syndrome characterized by multiple bone infarctions, cortical thickening, pathologic fractures, and a strong predisposition to an uncommon, highly malignant sarcoma. The etiology of HBD is unknown. Although rare, HBD is of particular interest because its gene defect not only results in abnormal bone formation, but also may cause sporadic sarcomas. Thus, the proposed research is directed to identify the HBD gene and to define its role in normal bone metabolism and in the pathogenesis of HBD and sarcoma. Dr. Martignetti recently initiated studies to identify the disease- causing gene which requires that he master the approaches and techniques of positional cloning. During his fellowship, he obtained DNA samples from three large HBD kindreds and performed a genome-wide search using microsatellite markers. The HBD locus was mapped to a 3 cM region at chromosome 9p21-22, a region previously implicated in the formation of a variety of tumors. To facilitate the isolation of the HBD gene: 1) the HBD linked region will be narrowed by identifying new family members and kindreds and analyzing the recombinants with additional markers; 2) a physical map of the region will be assembled using YAC, P1 and/or BAC clones; 3) candidate genes and ESTs mapping within the HBD region as defined by the physical map will be localized and evaluated; 4) the HBD gene will be identified using exon trapping, LOH analysis, and mutation analysis techniques; 5) the function of the HBD gene will be characterized to determine its function in normal bone metabolism and physiology and its role in causing HBD and tumorigenesis; and 6) the natural history, clinical variability and spectrum of manifestations of HBD will be delineated to gain additional insights into the disease, its pathogenesis, and the function of the HBD gene. Dr. Martignetti's development will be supported with protected research time, dedicated laboratory space, and Departmental and Institutional core facilities. He will be guided in the responsible conduct of research, and his development into an independent researcher will be enhanced by the serious involvement and commitment of his mentors and by the superb research and intellectual environment at Mount Sinai.

此应用程序旨在为 John Martignetti 博士提供一个程序 指导实验室研究，以促进他作为一名 独立医师科学家。 完成儿科学业后 遗传学奖学金，他将成为人类学助理教授 七月在西奈山医学院进行遗传学和儿科课程 1998年1月1日，他最近诊断出一个家族患有罕见的遗传性骨骼疾病 发育不良/癌症综合征，遗传性骨发育不良（HBD） 恶性变化，一种以多发性骨为特征的综合征 梗塞、皮质增厚、病理性骨折和强 易患罕见的高度恶性肉瘤。 病因学 HBD 未知。 虽然很少见，但 HBD 特别令人感兴趣，因为 其基因缺陷不仅导致骨形成异常，而且 可能会引起散发性肉瘤。 因此，所提出的研究方向是 鉴定 HBD 基因并确定其在正常骨中的作用 代谢以及 HBD 和肉瘤的发病机制。 Martignetti 博士最近发起了一项研究来确定这种疾病—— 造成基因需要他掌握方法和技术 的定位克隆。 在他的研究期间，他获得了DNA样本 来自三个大型 HBD 家族，并使用以下方法进行了全基因组搜索： 微卫星标记。 HBD 基因座被映射到 3 cM 区域 染色体 9p21-22，先前参与形成的区域 各种肿瘤。为了促进HBD基因的分离：1) 通过识别新的家庭成员和 亲属并用附加标记分析重组体； 2）一个 该区域的物理地图将使用 YAC、P1 和/或 BAC 进行组装 克隆； 3) HBD区域内的候选基因和ESTs映射为 物理图定义的将被本地化和评估； 4）HBD 将使用外显子捕获、LOH 分析和突变来识别基因 分析技术； 5) HBD基因的功能是 确定其在正常骨代谢中的功能和 生理学及其在引起 HBD 和肿瘤发生中的作用；和 6) 自然史、临床变异性和表现谱 将对 HBD 进行描述，以获得对该疾病及其影响的更多了解 发病机制和 HBD 基因的功能。 Martignetti 博士的发展将得到受保护研究的支持 时间、专用实验室空间以及部门和机构 核心设施。 他将受到指导，采取负责任的行为 研究，他将成为一名独立的研究员 他的导师的认真参与和承诺增强了 得益于西奈山一流的研究和智力环境。