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Modeling of Hyperparathyroidism-Jaw Tumor Syndrome by Targeted Deletion of Hrpt2

通过靶向删除 Hrpt2 来模拟甲状旁腺功能亢进症-颌骨肿瘤综合征

基本信息

批准号：
8299991
负责人：
Jessica Costa
金额：
$ 0.91万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2012-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8299991
关键词：
Address Adult Affect Animals Benign Body part Bone neoplasms Calcium Cancer Etiology Cancerous Clinical Cystic kidney Development Disease Endocrine System Diseases Genes Genetic Genetically Engineered Mouse Germ-Line Mutation Hamartoma Histologic Hormones Human Hyperparathyroidism Immature Bone In Vitro Individual Intervention Jaw Kidney Kidney Neoplasms Knock-out Knockout Mice Lesion Malignant - descriptor Malignant Neoplasms Mandible Maxilla Metaplastic Modeling Molecular Mouse Strains Mus Mutation Neoplasms Nephroblastoma Neural Crest Neural Crest Cell Organ Ossifying Fibroma Parathyroid Adenoma Parathyroid Gland Adenocarcinoma Parathyroid Neoplasms Parathyroid gland Pathogenesis Patients Periodontal Ligament Phenotype Process Research Research Design Serum Site Somatic Mutation Syndrome System Testing Tissues Transgenic Mice Tumor Suppressor Genes Uterine Cancer Uterus base bone cancer type fibroma insight kindred malignant parathyroid gland tumor mandible/maxilla mortality mouse model novel diagnostics offspring promoter recombinase treatment strategy tumor

项目摘要

Hyperparathyroidism jaw-tumor syndrome (HPT-JT) is a syndrome that predisposes individuals to the development of one or more benign or malignant parathyroid tumors, ossifying fibromas of the mandible and/or maxilla, benign or malignant uterine tumors and, less commonly, cystic kidney lesions, renal hamartomas or Wilm's tumors. Affected individuals may develop multiple primary parathyroid, jaw, uterine and/or kidney tumors over the course of their lifetime. Inactivating mutations of theHRPT2 tumor suppressor gene (also called CDC73), encoding parafibromin, were identified as the genetic cause of HPT-JT in the majority of affected kindreds. Subsequently, screens of sporadic parathyroid carcinomas, ossifying fibromas of the mandible and renal tumors revealed both germline and somatic mutations of HRPT2. The proposed studies are designed to address the mechanisms through which loss of Hrpt2/parafibromin promotes neoplasia in the parathyroid glands and jaws, in the pathophysiologically relevant experimental context of an intact animal. To study the pathophysiological consequences of knockout of Hrpt2 in vitro, genetically- engineered mice in which the Hrpt2 gene is flanked by two loxP sites have been generated and will be crossed with two different transgenic mouse strains, PTH-Cre and Wnt1-Cre. These crosses will result in offspring with Hrpt2 deletion in the parathyroid glands or mandible, respectively. Development of these two mouse models will provide a means for dissecting the molecular basis of HPT-JT, sporadic parathyroid tumors and ossifying jaw fibromas and may ultimately enable the development of new diagnostic and treatment strategies.

甲状旁腺功能亢进颌骨肿瘤综合征（HPT-JT）是一种综合征，使个体易患一种或多种良性或恶性甲状旁腺肿瘤、下颌骨和/或上颌骨骨化纤维瘤、良性或恶性子宫肿瘤，以及较少见的囊性肾病变、肾错构瘤或威尔姆氏瘤。受影响的个体可能在其一生中发展多发性原发性甲状旁腺、颌骨、子宫和/或肾脏肿瘤。编码parafibromin的hrpt2肿瘤抑制基因（也称为CDC73）失活突变被确定为大多数受影响种类中HPT-JT的遗传原因。随后，散发性甲状旁腺癌、下颌骨骨化纤维瘤和肾脏肿瘤的筛查显示HRPT2的种系和体细胞突变。在完整动物的病理生理学相关实验背景下，拟议的研究旨在解决Hrpt2/parafibromin缺失促进甲状旁腺和颌骨肿瘤形成的机制。为了在体外研究Hrpt2基因敲除的病理生理后果，我们培育了Hrpt2基因两侧有两个loxP位点的基因工程小鼠，并将其与两种不同的转基因小鼠品系PTH-Cre和Wnt1-Cre杂交。这些杂交将导致在甲状旁腺或下颌骨分别有Hrpt2缺失的后代。这两种小鼠模型的建立将为解剖HPT-JT、散发性甲状旁腺瘤和骨化性颌骨纤维瘤的分子基础提供手段，并可能最终促进新的诊断和治疗策略的发展。