Chemoprevention of pituitary gonadotrope tumors

垂体促性腺激素肿瘤的化学预防

• 批准号: 8439002
• 负责人: T. RAJENDRA KUMAR
• 金额: $ 31.33万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8439002
• 关键词: Acute; Antiestrogen Therapy; Biological Markers; Biological Models; Blindness; Carcinoma; Chemoprevention; Chemopreventive Agent; Clinical; Confocal Microscopy; Data; Development; Diagnostic; Early Diagnosis; Erinaceidae; Estrogen Antagonists; Estrogen Receptor 1; Estrogen Receptors; Estrogen Therapy; Estrogens; Failure; Follicle Stimulating Hormone; Frequencies; Gene Expression Profiling; General Population; Glycoproteins; Goals; Green Fluorescent Proteins; Growth; Headache; Hemorrhage; Hormones; Human; Hypopituitarism; In Vitro; Intracranial Hypertension; Intracranial Neoplasms; Itraconazole; Knowledge; Label; Lasers; Luteinizing Hormone; Messenger RNA; MicroRNAs; Mission; Mitogen-Activated Protein Kinases; Molecular Profiling; Mouse Strains; Mus; Nausea; Neurologic; Null Lymphocytes; Operative Surgical Procedures; Optic Chiasm; Pathogenesis; Pathway interactions; Patients; Phenocopy; Phosphorylation; Pituitary Diseases; Pituitary Gland; Pituitary Gland Adenoma; Pituitary Neoplasms; Prevalence; Prevention; Preventive; Production; Public Health; Receptor Signaling; Recurrence; Research; Signal Transduction; Sorting - Cell Movement; Staging; Symptoms; Tamoxifen; Testing; Time; Transgenic Mice; Transgenic Organisms; adenoma; base; brain tissue; clinically relevant; cyclopamine; cytokine; disability; efficacy testing; glycosylation; in vivo; in vivo Model; inhibitor/antagonist; innovation; insight; mouse model; novel; overexpression; public health relevance; sex; smoothened signaling pathway; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Pituitary adenomas are the most frequent of all pituitary diseases and are observed in both sexes. The prevalence is estimated as ~90 cases per 105 people. The majority arises from the gonadotrope lineage and these tumors do not hypersecrete glycoprotein hormones [i.e., luteinizing hormone (LH) and follicle stimulating hormone (FSH)] and thus are called null cell adenomas. The clinical manifestations include neurological symptoms such as damage to brain tissue and optic chiasm, vision loss, increased intracranial pressure, persistent headache and nausea. Because they have no well-defined diagnostic markers, null cell adenomas often go undetected until they are very advanced and surgery is the only treatment. There are no established model systems or chemoprevention options available for null cell adenomas. We have developed a unique transgenic strain of mice that develops gonadotrope-enriched pituitary adenomas and phenocopies human pituitary null cell adenomas including. Our long-term goal is to understand the mechanisms of origin and progression of null cell adenoma, and develop new strategies of chemoprevention for it. The objective of this proposal is to identify biomarkers and specific targets/pathways responsible for gonadotrope tumor progression such that mechanistic insights into progression and prevention of human null cell adenomas could ultimately be obtained. Our central hypothesis is that both estrogen receptor-1 (ESR1) and Indian hedgehog (IHH) contribute to growth of pituitary gonadotrope adenomas and inhibiting their expression leads to clinical benefit. In Specific Aim 1, we will determine the mechanism by which estrogen signaling influences tumor growth and progression. Effects of estrogen on glycosylation that contribute to hormone secretion failure will be evaluated. Additionally, a novel mouse model in which gonadotrope tumors are fluorescently labeled will be used to identify potential biomarkers. In Specific Aim 2, we will test the efficacyof anti-estrogen therapy to regulate gonadotrope tumor growth. The approach involves the use of mice conditionally overexpressing Esr1 at desired times, and mice lacking either Esr1 or Esr2 on the tumor-prone transgenic background. The in vivo tumor preventive effects of tamoxifen will also be tested. In Specific Aim 3, we will determine the effects of blocking IHH action on gonadotrope tumor development. We will specifically delete Ihh in gonadotrope tumors by using a cre-lox approach. In a second approach, the effects of hedgehog chemoprevention agents will be tested in gonadotrope tumors of transgenic mice. The approach is innovative, because it utilizes a unique transgenic mouse model that develops gonadotrope tumors and uses a combination of in vitro and novel in vivo models. The proposed research is significant because it is expected to vertically advance and expand understanding of how chemopreventive agents targeted to block estrogen and hedgehog signaling regulate gonadotrope/null cell adenomas.

描述（由申请人提供）：垂体腺瘤是所有垂体疾病中最常见的，并且在男女中均可观察到。患病率估计为每 105 人约 90 例。大多数来自促性腺激素谱系，这些肿瘤不会过度分泌糖蛋白激素[即黄体生成素（LH）和卵泡刺激素（FSH）]，因此被称为无效细胞腺瘤。临床表现包括脑组织和视交叉损伤、视力丧失、颅内压增高、持续性头痛和恶心等神经系统症状。由于没有明确的诊断标志物，空细胞腺瘤通常不会被检测到，直到它们已经发展到非常晚期并且手术是唯一的治疗方法。目前还没有针对无效细胞腺瘤的既定模型系统或化学预防方案。我们开发了一种独特的转基因小鼠品系，可产生富含促性腺激素的垂体腺瘤，并复制人类垂体无效细胞腺瘤的表型。我们的长期目标是了解空细胞腺瘤的起源和进展机制，并为其制定新的化学预防策略。该提案的目的是确定负责促性腺激素肿瘤进展的生物标志物和特定靶点/途径，以便最终获得对人类空细胞腺瘤进展和预防的机制见解。我们的中心假设是雌激素受体 1 (ESR1) 和印度刺猬蛋白 (IHH) 均有助于垂体促性腺激素腺瘤的生长，抑制其表达可带来临床益处。在具体目标 1 中，我们将确定雌激素信号传导影响肿瘤生长和进展的机制。雌激素对糖基化的影响会导致激素分泌失败 进行评估。此外，一种新的小鼠模型，其中促性腺激素肿瘤被荧光标记，将用于识别潜在的生物标志物。在具体目标 2 中，我们将测试抗雌激素疗法调节促性腺激素肿瘤生长的功效。该方法涉及使用在所需时间条件性过度表达 Esr1 的小鼠，以及在易患肿瘤的转基因背景下缺乏 Esr1 或 Esr2 的小鼠。他莫昔芬的体内肿瘤预防作用也将得到测试。在具体目标 3 中，我们将确定阻断 IHH 作用对促性腺激素肿瘤发展的影响。我们将通过使用 cre-lox 方法专门删除促性腺激素肿瘤中的 Ihh。在第二种方法中，将在转基因小鼠的促性腺激素肿瘤中测试刺猬化学预防剂的效果。该方法具有创新性，因为它利用独特的转基因小鼠模型来开发促性腺激素肿瘤，并结合使用体外和新颖的体内模型。拟议的研究意义重大，因为它有望垂直推进和扩大对靶向阻断雌激素和刺猬信号传导的化学预防剂如何调节促性腺激素/无效细胞腺瘤的理解。