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

描述(申请人提供)：甲状旁腺功能亢进症颌骨肿瘤综合征(HPT-JT)是一种易患上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损害、肾错构瘤或肾母细胞瘤的综合征。受影响的人在一生中可能会患上多种原发甲状旁腺、颌骨、子宫和/或肾脏肿瘤。编码副纤维蛋白的HRPT2抑癌基因(也称为CDC73)的失活突变被认为是大多数HPT-JT家系的遗传原因。随后，对散发性甲状旁腺癌、下颌骨骨化纤维瘤和肾脏肿瘤的筛查发现了HRPT2的胚系和体细胞突变。这项拟议的研究旨在探讨在完整动物的病理生理学相关实验背景下，Hrpt2/副纤维蛋白缺失促进甲状旁腺和颌骨肿瘤的机制。为了在体外研究Hrpt2基因敲除的病理生理后果，已经建立了Hrpt2基因两侧带有两个loxP位点的基因工程小鼠，并将其与两个不同的转基因小鼠品系PTH-Cre和Wnt1-Cre杂交。这些杂交将导致后代分别在甲状旁腺或下颌中缺失Hrpt2。这两种小鼠模型的发展将为解剖HPT-JT、散发性甲状旁腺肿瘤和骨化性颌骨纤维瘤的分子基础提供一种手段，并最终可能使新的诊断和治疗策略的开发成为可能。

DESCRIPTION (provided by applicant): 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.