Mechanisms of Pituitary Tumorigenesis

垂体肿瘤发生机制

基本信息

批准号：
7847469
负责人：
SHLOMO MELMED
金额：
$ 28.57万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-12-15 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7847469
关键词：
Accounting Adrenal Gland Hyperfunction Adrenal Glands Aneuploidy Benign Cell Culture Techniques Cell Cycle Cell Cycle Arrest Cell Cycle Checkpoint Cell Cycle Proteins Cell Cycle Regulation Cell Proliferation Cells Chromosomal Instability Clinical Corticotropin DNA Damage Development E2F1 gene Endocrine Syndrome Estrogens Failure Functional disorder G1 Phase Gene Expression Genetic Genetic Models Genetic Transcription Genotype Gonadotropins Growth Growth Disorders Heterozygote Hormonal Hormones Human Hyperplasia In Vitro Infertility Intracranial Neoplasms Knock-in Mouse Link Malignant - descriptor Malignant Neoplasms Measures Mediating Mediator of activation protein Metabolic Mitosis Modeling Mus Neoplasms PTTG1 gene Pathogenesis Pathway interactions Penetrance Pituitary Diseases Pituitary Gland Pituitary Gland Adenoma Pituitary Neoplasms Pituitary carcinoma Pregnancy Prolactin Property Proteins Rattus Role Sister Chromatid Somatotropin Somatotropin-Releasing Hormone Structure TP53 gene Testing Thyroid Gland Tissues Transgenic Model Tumor Cell Line adenoma base cancer cell gonad function hormone regulation human PTTG1 protein improved inhibitor/antagonist insight mutant neoplastic cell premature protein expression protein function public health relevance research study senescence tumor tumor growth tumorigenesis

项目摘要

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.

描述（由申请人提供）：垂体肿瘤占颅内肿瘤的15％，是良性的单克隆肿瘤，可能在临床上保持沉默或分泌激素，包括催乳素，生长激素，ACTH或急性TSH或TSH或Gonadotropins。这些腺瘤解释了与垂体性低居性相关的临床不育症，生长障碍以及过度皮质醇或代谢功能障碍。该建议旨在探索垂体细胞增殖的无序加剧控制在这些良性腺瘤的发病机理中的作用。在第一个目的中，我们将研究垂体性非整倍性，过早的增殖（衰老），细胞增殖的标志物以及鼠垂体症状肿瘤转基因模型（1GSU.PTTG和RB杂合子）中的肿瘤发生的机制。在这些基因型和垂体细胞培养物中，将研究遗传和荷尔蒙诱导的垂体诱导性肿瘤发生的机制。在第二个目标中，我们将研究人垂体肿瘤中的DNA损伤，非整倍性的细胞标记和衰老介质。在第三个目标中，我们将通过评估RB小鼠中PTTG转录和蛋白质表达的E2F1诱导RB/E2F诱导垂体肿瘤的机制。这些实验的结果将进一步了解实验和人垂体肿瘤的细胞周期控制和生长约束的作用，从而无法发展为恶性肿瘤。结果将提高我们对与不育，生长障碍，高皮层溶质或肾上腺，甲状腺和性腺衰竭有关的临床内分泌综合征的理解。公共卫生相关性：该项目将研究实验性垂体肿瘤模型的生长控制，以及分泌或临床非分泌的人垂体肿瘤。这些实验将洞悉不育，生长障碍或过度皮质醇的发展的机制，以及由于垂体功能无序而导致的甲状腺，肾上腺或性腺功能的失败。