MOLECULAR PATHOGENESIS OF PARATHYROID NEOPLASIA

具体地说，拟议研究的长期目标是 识别和鉴定在生物多样性研究中起重要作用的基因 人类甲状旁腺肿瘤的发病机制(腺瘤和 癌症)。尽管这些基因中的大多数还没有 细胞的鉴定、基因重排和过表达 细胞周期调节因子(PRAD1或人类细胞周期蛋白D1)与 大约5%的甲状旁腺肿瘤的发病机制。潜在的 那么，提议的研究的假设是，在 其他细胞周期调节因子(P53、视网膜母细胞瘤和细胞周期蛋白 除PRAD1之外)和/或其他候选癌基因(一些 可能是由于它们的过度表达)可能在 这些肿瘤的发病机制。为了开始检验这一假设， 人类甲状旁腺腺瘤将被检查：(I)异常 在p53和Rb基因中使用“杂合性缺失”(LOH) 对剩余的、非 表现为LOH的肿瘤中的缺失等位基因；和(IL)肿瘤特异性 CDNA的过度表达(或唯一表达) 消减杂交，其中一个或多个可能编码一个 推定的癌基因或功能上与癌基因连锁的基因。 这些研究应该会提供对分子的重要见解。 这些肿瘤的发生机制，并可能 可能会产生更广泛的临床和生物学影响 PRAD1就是这种情况)。

Specifically, the long-term objective of the proposed research is to identify and characterize genes that are important in the pathogenesis of human parathyroid neoplasms (both adenomas and carcinomas). Although the majority of these genes have yet to be identified, genetic rearrangement and overexpression of a cell cycle regulator (PRAD1 or human cyclin D1) has been implicated in the pathogenesis of about 5% of parathyroid tumors. The underlying hypothesis for the proposed studies, then, is that abnormalities in other cell cycle regulators (p53, retinoblastoma (Rb) and cyclins other than PRAD1) and/or additional candidate oncogenes (some perhaps by their overexpression) are likely to be important in the pathogenesis of these tumors. To begin to test this hypothesis, human parathyroid adenomas will be examined for: (i) abnormalities in the p53 and Rb genes using "loss of heterozygosity" (LOH) studies and subsequent characterization of the remaining, non- deleted allele in tumors showing LOH; and (il) tumor-specific overexpression (or unique expression) of cDNAs isolated by subtractive hybridization, one or more of which may encode a putative oncogene or a gene functionally linked to an oncogene. These studies should provide important insights into the molecular mechanisms of tumorigenesis in these neoplasms, and could potentially have broader clinical and biological ramifications as has been the case for PRAD1).