Mechanisms of Pituitary Tumorigenesis

描述（由申请方提供）：垂体瘤占颅内肿瘤的15%，是良性单克隆肿瘤，可能临床上无症状或分泌激素，包括催乳素、生长激素、ACTH或罕见的TSH或促性腺激素。这些腺瘤导致临床不孕、生长障碍和皮质醇增多症或与垂体功能减退相关的代谢功能障碍。该建议旨在探讨垂体细胞增殖控制紊乱在这些良性腺瘤发病机制中的作用。在第一个目标中，我们将在小鼠垂体瘤转基因模型（1GSU、PTTG和Rb杂合子）中研究垂体非整倍体、过早增殖停滞（衰老）、细胞增殖标记物和肿瘤发生的机制。将在这些基因型和垂体细胞培养中研究遗传和垂体诱导的垂体肿瘤发生机制。在第二个目标中，我们将研究人垂体瘤中的DNA损伤、非整倍体的细胞标志物和衰老介质。在第三个目标中，我们将研究Rb/E2 F诱导垂体瘤的机制，通过评估E2 F1诱导Rb小鼠，缺乏p53或p21的突变型人类癌细胞以及人类垂体腺瘤中的Pttg转录和蛋白表达。这些实验的结果将使人们能够进一步了解实验性和人类垂体瘤的细胞周期控制和生长限制的作用，这是它们未能进展为恶性肿瘤的基础。这些结果将提高我们对与不孕症、生长障碍、皮质醇增多症或由于垂体功能丧失导致的肾上腺、甲状腺和性腺衰竭相关的临床内分泌综合征的理解。公共卫生相关性：本项目将研究实验性垂体瘤模型的生长控制，以及分泌垂体瘤或临床上不分泌垂体瘤的人垂体瘤。这些实验将深入了解不孕症、生长障碍或皮质醇增多症以及由于垂体功能紊乱导致的甲状腺、肾上腺或性腺功能衰竭的潜在机制。

DESCRIPTION (provided by applicant): Pituitary tumors account for 15% of intracranial neoplasms and are benign monoclonal neoplasms which may be clinically silent or secrete hormones including prolactin, growth hormone, ACTH, or rarely TSH or gonadotropins. These adenomas account for clinical infertility, growth disorders and hypercortisolism or metabolic dysfunctions associated with hypo-pituitarism. This proposal is aimed at exploring the role of disordered pituitary cell proliferation control in the pathogenesis of these invariably benign adenomas. In the first Aim, we will study mechanisms underlying pituitary aneuploidy, premature proliferative arrest (senescence), markers of cell proliferation and tumorigenesis in transgenic models of murine pituitary tumors (1GSU.PTTG and Rb heterozygotes). Mechanisms for both genetic and hormonally induced pituitary tumorigenesis will be studied in these genotypes and in pituitary cell cultures. In the second Aim we will study DNA damage, cellular markers of aneuploidy and senescent mediators in human pituitary tumors. In the third Aim we will study mechanisms for Rb/E2F induction of pituitary tumors by assessing E2F1 induction of Pttg transcription and protein expression in Rb mice, in mutant human cancer cells devoid of p53 or p21, as well as in human pituitary adenomas. Results of these experiments will enable further insights into the role of cell cycle control and growth constraint of experimental and human pituitary tumors, underlying their failure to progress to malignancy. The results will improve our understanding of clinical endocrine syndromes associated with infertility, growth disorders, hypercortisolism or adrenal, thyroid and gonadal failure due to abrogated pituitary function. PUBLIC HEALTH RELEVANCE: This project will study growth control of experimental pituitary tumor models, as well as hormone-secreting or clinically non-secreting human pituitary tumors. These experiments will provide insight into mechanisms underlying development of infertility, growth disorders or hypercortisolism, as well as failure of thyroid, adrenal or gonadal function due to disordered pituitary function.