MECHANISMS FOR PITUITARY TUMORIGENESIS

垂体肿瘤发生机制

• 批准号: 6624736
• 负责人: SHLOMO MELMED
• 金额: $ 25.51万
• 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/6624736
• 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.

垂体腺瘤是一种常见的良性肿瘤，可引起 生长、生殖功能、皮质醇产生和地方中枢 压力效应。尽管最近被确定为单克隆性，但 参与垂体细胞转化的遗传机制尚不清楚。 这一建议将表征PTTG的变换性质，a 新的脑垂体瘤衍生蛋白。我们使用差异RNA显示技术 大鼠脑垂体源转化基因(PTTG)的鉴定 公元199年。新的蛋白质。现在，我们将分离和研究人类PTTG和 确定它的染色体位置。PTTG的表达将在激素- 分泌性(PRL、GH、ACTH)和无功能垂体瘤及其 丰度被评估为垂体腺瘤分级的函数， 侵袭性激素、荷尔蒙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法确定 双重免疫染色和原位技术。垂体腺模型 肥大(妊娠和雌激素诱导的催乳素瘤)将用于 测定PTTG在垂体细胞发病机制中的表达 增生到腺瘤形成。PTTG的体外转化和体内转化 特性将在双琼脂转化试验中确定，裸露 将评估小鼠的肿瘤形成和生长因子调节。效应 还将评估可诱导的PTTG表达对细胞增殖的影响。 因此，这些研究将提供对发病机制的深入了解。 催乳素瘤、肢端肥大症、库欣病和无分泌性疾病 脑垂体瘤。