MOLECULAR PATHOGENESIS OF PARATHYROID NEOPLASIA

甲状旁腺肿瘤的分子发病机制

• 批准号: 2084409
• 负责人: VINCENT L. CRYNS
• 金额: $ 8.08万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2084409
• 关键词: adenoma; carcinoma; cell cycle proteins; complementary DNA; gene expression; gene rearrangement; genetic library; human subject; loss of heterozygosity; neoplasm /cancer genetics; neoplastic transformation; oncogenes; parathyroid hyperplasia; parathyroid neoplasms; restriction fragment length polymorphism; subtraction hybridization; tumor suppressor genes

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).

具体而言，拟议研究的长期目标是 来识别和表征在人类免疫系统中重要的基因， 人甲状旁腺肿瘤（腺瘤和 癌）。尽管这些基因中的大多数还没有被 细胞的基因重排和过表达 细胞周期调节因子（PRAD 1或人细胞周期蛋白D1）参与了 约5%的甲状旁腺肿瘤的发病机制。底层 因此，拟议研究的假设是， 其他细胞周期调节因子（p53、视网膜母细胞瘤（Rb）和细胞周期蛋白 除PRAD 1外）和/或其他候选癌基因（一些 也许是通过它们的过度表达）可能在 这些肿瘤的发病机制。为了开始检验这个假设， 将检查人甲状旁腺腺瘤的：（i）异常 在p53和Rb基因中使用“杂合性丢失”（洛） 研究和随后的表征，其余的，非 肿瘤中缺失的等位基因显示洛;和（ii）肿瘤特异性 过表达（或独特表达）的cDNA分离， 消减杂交，其中的一个或多个可以编码 假定的癌基因或与癌基因功能性连锁的基因。 这些研究应该提供重要的见解， 这些肿瘤的肿瘤发生机制， 可能具有更广泛的临床和生物学影响， PRAD 1的情况）。