ISOLATION OF GENES FOR PAGET DISEASE AND OSTEOSARCOMA

描述(改编自申请者摘要)：佩吉特病 骨是一种常见的骨病，其特征是破骨细胞异常 是大的，过度活跃的，多核的，含有副粘病毒样的核 包裹体。这是一种相对常见的疾病，估计发病率 在40岁以上的个人中为3%。在大多数患者中，Paget 疾病是无症状的。有症状的患者中有5%有骨痛 以及广泛的并发症，包括骨折增加，耳聋 和神经系统并发症。Paget最具破坏性的并发症 疾病是骨骼的恶性转化。尽管这些 转化是罕见的，它们极大地导致了发病率和 这种疾病的死亡率。最常见的恶性肿瘤类型 与Paget病相关的转化是骨肉瘤。此外, Paget骨肉瘤患者的预后比患者差得多 患有新发骨肉瘤。骨肉瘤被认为是由一种 一系列将成骨细胞转化为恶性细胞的基因改变 州政府。强有力的证据表明，一个重要的肿瘤抑制基因参与了 成骨细胞的调控位于18号染色体上，最近 (马克·汉森博士的实验室)。此外，申请人(Dr。 LEACH)已经产生了遗传证据，表明存在Paget的基因座 疾病在18号染色体的同一区域。因此，两者之间的相关性 Paget病和骨肉瘤有很强的分子基础。它是 假设这个骨肉瘤抑癌基因和Paget 易感基因是相同的基因，或者是两个紧密连锁的基因(即 邻接基因综合征)。这项研究的目标就是确定这一点 18号染色体上的基因(或这些基因)，并开始确定它们在 这两种疾病都有。这项建议是互动研究的一部分 项目赠款(IRPG)是为实现这一目标而开发的。汉森医生的 实验室将在骨肉瘤中使用有丝分裂图谱方法，而Dr。 利奇的实验室将对许多Paget病使用减数分裂图谱 一家亲。鉴定这个基因(或这些基因)是重要的一步。 对于骨肉瘤和Paget病的治疗的发展。

DESCRIPTION (Adapted from the Applicant's Abstract): Paget disease of the bone is a common bone disease characterized by abnormal osteoclasts which are large, overactive, multinucleated and contain paramyxovirus-like nuclear inclusions. It is a relatively common disorder, with an estimated incidence of 3% in individuals over the age of 40. In the majority of patients, Paget disease is asymptomatic. The 5% of patients with symptoms have bone pain and a wide range of complications including increased fractures, deafness and neurological complications. The most devastating complication of Paget disease is malignant transformation of the bone. Although these transformations are rare, they contribute significantly to the morbidity and mortality of this disorder. The most frequent type of malignant transformation associated with Paget disease is osteosarcoma. In addition, Paget patients with osteosarcoma have a much worse prognosis than patients with osteosarcoma de novo. Osteosarcomas are believed to result from a series of genetic alterations which transform the osteoblast to a malignant state. Strong evidence that an important tumor suppressor gene involved in the regulation of the osteoblast lies on chromosome 18 has recently been generated (Dr. Marc Hansen's laboratory). Furthermore, the applicant (Dr. Leach) has generated genetic evidence that there is a locus for Paget disease in the same region of chromosome 18. Thus, the correlation between Paget disease and osteosarcoma has a strong molecular basis. It is hypothesized that this osteosarcoma tumor suppressor gene and the Paget predisposition gene are the same gene, or two tightly linked genes (i.e., a contiguous gene syndrome). The goal of this research is to identify this gene (or these genes) on chromosome 18 and begin to determine their role in both of these disorders. This proposal is part of an Interactive Research Project Grant (IRPG) developed to achieve this goal. Dr. Hansen's laboratory will utilize mitotic mapping methods in osteosarcomas, while Dr. Leach's laboratory will use meiotic mapping with numerous Paget disease kindreds. Identification of this gene (or these genes) is an important step towards the development of treatment for osteosarcoma and Paget disease.