Chemoprevention of pituitary gonadotrope tumors

垂体促性腺激素肿瘤的化学预防

基本信息

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
项目类别：
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

项目摘要

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，并且在两性中都观察到。患病率估计为每105人约90例。多数是由促性腺瘤谱系引起的，这些肿瘤不催眠糖蛋白激素[即黄体激素（LH）和卵泡刺激激素（FSH）]，因此称为Null细胞腺瘤。临床表现包括神经系统症状，例如对脑组织的损害和视神经障碍，视力丧失，颅内压增加，头痛持续性头痛和恶心。由于它们没有明确定义的诊断标记，因此无效的细胞腺瘤通常一直未被发现，直到他们非常先进，并且手术是唯一的治疗方法。没有既定的模型系统或化学预防选项可用于零细胞腺瘤。我们已经开发了一种独特的转基因小鼠菌株，该菌株发展了促性腺源性垂体腺瘤和表型人类垂体无效的无效细胞腺瘤。我们的长期目标是了解零细胞腺瘤的起源和进展的机制，并为其制定新的化学预防策略。该提案的目的是确定导致性腺肿瘤进展的生物标志物和特定靶标/途径，以便最终可以获得机械洞察到对人类无效细胞腺瘤的进展和预防的见解。我们的中心假设是，雌激素受体-1（ESR1）和印度刺猬（IHH）均有助于垂体性腺体腺瘤的生长，并抑制其表达导致临床益处。在特定目标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。雌激素对导致激素分泌衰竭的糖基化的影响将进行评估。此外，一种新型的小鼠模型，其中促性腺肿瘤被荧光标记为鉴定潜在的生物标志物。在特定的目标2中，我们将测试抗雌激素治疗的效率以调节促性腺肿瘤的生长。该方法涉及在所需时间有条件地过表达ESR1的小鼠，而在易于肿瘤的转基因背景上缺乏ESR1或ESR2的小鼠。他莫昔芬的体内肿瘤预防作用也将进行测试。在特定目标3中，我们将确定阻断IHH作用对促性腺肿瘤发育的影响。我们将使用CRE-LOX方法专门删除促性腺肿瘤中的IHH。在第二种方法中，刺猬化学预防剂的作用将在转基因小鼠的性腺肿瘤中进行测试。该方法具有创新性，因为它利用了一种独特的转基因小鼠模型，该模型会发展出促性腺肿瘤并结合体外体内模型的组合。拟议的研究很重要，因为预计它将垂直提高和扩展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性腺/无效细胞腺瘤的理解。