GENETIC DISSECTION OF A BONE DYSPLASIA/CANCER SYNDROME

此应用程序旨在为约翰·马蒂涅蒂博士提供一个程序 指导实验室研究，以促进他的发展， 独立的物理学家和科学家 在完成了他的儿科 遗传学奖学金，他将成为人类学助理教授 遗传学和儿科学在西奈山医学院7月 1，1998年。 他最近诊断出一个家庭患有一种罕见的遗传性骨骼 发育不良/癌症综合征，遗传性骨发育不良（HBD）， 恶变，一种以多发性骨 梗死，皮质增厚，病理性骨折，以及强烈的 易患罕见的高度恶性肉瘤 病因 HBD是未知的。 虽然罕见，但HBD特别令人感兴趣，因为 它的基因缺陷不仅导致骨形成异常， 可能会导致散发性肉瘤 因此，建议的研究是针对 确定HBD基因并确定其在正常骨骼中的作用 代谢和HBD和肉瘤的发病机制。 博士Martignetti最近发起了一项研究，以确定这种疾病- 这就要求他掌握方法和技术， 定位克隆。 在他的研究期间，他获得了DNA样本 从三个大的HBD激酶，并进行了全基因组搜索， 微卫星标记 HBD基因座定位于3cM区域， 染色体9 p21 -22，一个以前参与形成的区域， 各种各样的肿瘤为了促进HBD基因的分离：1） HBD连锁区域将通过识别新的家族成员来缩小， 用另外的标记物激动和分析重组体; 2） 该地区的物理地图将使用YAC、P1和/或BAC进行组装 3）HBD区域内的候选基因和EST， 物理地图定义的将被定位和评估; 4）HBD 将使用外显子捕获、洛分析和突变来鉴定基因 分析技术; 5）HBD基因的功能将 其特征在于确定其在正常骨代谢中的功能， 生理学及其在引起HBD和肿瘤发生中的作用;以及6） 自然史，临床变异性和表现谱 HBD将被划定，以获得更多的见解，疾病，其 发病机制和HBD基因的功能。 博士Martignetti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 他将在负责任的行为， 他将成为一名独立的研究人员， 通过他的导师的认真参与和承诺， 西奈山一流的研究和智力环境。

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.