MECHANISMS FOR PITUITARY TUMORIGENESIS

垂体肿瘤发生机制

• 批准号: 6328988
• 负责人: SHLOMO MELMED
• 金额: $ 24.42万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-15 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6328988
• 关键词: adenoma; athymic mouse; cell proliferation; cell transformation; chromosome walking; fibroblast growth factor; gene expression; genetic library; human genetic material tag; human tissue; hyperplasia; immunocytochemistry; in situ hybridization; laboratory rat; neoplasm /cancer genetics; neoplastic growth; neoplastic process; neoplastic transformation; northern blottings; oncogenes; oncoproteins; pituitary neoplasms; polymerase chain reaction; pregnancy; protein structure function

Pituitary adenomas are common benign neoplasms giving rise to disorders of growth, reproductive function, cortisol production and local central pressure effects. Although recently determined to be monoclonal, the genetic mechanisms involved in pituitary cell transformation are unclear. This proposal will characterize the transforming properties of PTTG, a novel pituitary tumor derived protein. We used differential RNA display to identify a rat pituitary derived transforming gene (PTTG) which encodes a 199 a.a. novel protein. Now, we will isolate and study human PTTG and assign its chromosomal locus. PTTG expression will be tested in hormone- secreting (PRL, GH, ACTH) and non-functional pituitary tumors, and its abundance assessed as a function of pituitary adenoma grading, invasinenes, hormonal activity and ultimately long-term clinical outcome. Cellular localization of PTTG will also be determined in these tumors by double immunostaining and in situ techniques. Models of pituitary enlargement (pregnancy and estrogen-induced prolactinomas) will be used to determine PTTG expression in the pathogenesis of the pituicyte to hyperplasia to adenoma formation. PTTG in vitro and in vivo transforming properties will be determined in double agar transformation assays, nude mouse tumorigenesis and growth factor regulation will be assessed. Effects of inducible PTTG expression on cell proliferation will also be assessed. These studies will thus provide mechanistic insight into the pathogenesis of prolactinomas, acromegaly, Cushing's Disease and non-secreting pituitary tumors.

垂体腺瘤是常见的良性肿瘤，可引起以下疾病 生长、生殖功能、皮质醇产生和局部中枢 压力影响。尽管最近确定为单克隆， 参与垂体细胞转化的遗传机制尚不清楚。 该提案将描述 PTTG 的转化特性，PTTG 是一种 新型垂体瘤衍生蛋白。我们使用差异RNA展示来 鉴定出大鼠垂体衍生的转化基因 (PTTG)，其编码 199 AA新型蛋白质。现在，我们将分离并研究人类PTTG和 指定其染色体位点。 PTTG 表达将在激素中进行测试 分泌型（PRL、GH、ACTH）和非功能性垂体瘤及其 丰度评估为垂体腺瘤分级的函数， invasinenes、激素活性和最终的长期临床结果。 PTTG 在这些肿瘤中的细胞定位也将通过以下方式确定： 双重免疫染色和原位技术。垂体模型 增大（怀孕和雌激素诱导的泌乳素瘤）将用于 确定垂体细胞发病机制中 PTTG 的表达 增生形成腺瘤。 PTTG体外和体内转化 性质将在双琼脂转化测定中确定，裸 将评估小鼠肿瘤发生和生长因子调节。效果 还将评估诱导型 PTTG 表达对细胞增殖的影响。 因此，这些研究将为发病机制提供机制上的见解 泌乳素瘤、肢端肥大症、库欣病和非分泌型 垂体肿瘤。