Innovative mouse model to study parathyroids and an application to human disease

描述(由申请人提供)：本申请涉及广泛的挑战领域(15)：翻译科学15-DK-102。建立改良的NIDDK病动物模型。甲状旁腺激素(PTH)是钙磷平衡和骨代谢最重要的调节剂之一。FGF23由骨骼分泌，是另一个重要的磷酸盐稳态调节因子。最近的数据表明，FGF23和PTH在骨-甲状旁腺轴上相互调节，然而，现有的数据是相互矛盾的，需要澄清。甲状旁腺细胞的分子调控研究进展非常缓慢，因为没有细胞系存在，腺体非常小，在体内进行分子分析几乎是不可能的。由于甲状旁腺功能障碍会导致软组织钙化、骨骼脆弱、慢性肾功能衰竭、肌病、心功能不全、血液学异常、软骨病和软骨病等严重后果，因此需要一种新的方法来解决这一问题。这项提议的总体目标是产生一种创新和独特的小鼠模型，该模型具有在甲状旁腺细胞表面稳定表达的逆转录病毒受体。然后，通过简单地在腹膜内注射逆转录病毒构建物，可以诱导这只小鼠表达不同的基因，包括仅在甲状旁腺中表达的siRNA。然后，可以单独或联合针对甲状旁腺靶向不同的基因，而不需要为每个结构产生新的转基因小鼠。我们还将把这一新模型应用于一种特定的遗传形式的甲状旁腺功能减退症(HP)。在两个具有显性-负性效应的常染色体显性遗传性甲状旁腺功能减退症(DnGCMB)家系中发现了新的GCMB杂合突变。我们将在甲状旁腺中表达野生型或dnGCMB，以确定其在出生后甲状旁腺中的作用。了解GCMB的作用可能有助于开发影响甲状旁腺功能的治疗剂，从而可用于多种疾病，包括原发性甲状旁腺功能亢进症(一种比HP更常见的疾病)，以及与慢性肾脏疾病相关的继发性甲状旁腺功能亢进症。这一创新的体内模型不仅有助于我们了解甲状旁腺的调节网络，而且将为其他系统的类似研究提供有用的模型。 公共卫生意义：甲状旁腺产生甲状旁腺激素(PTH)，这是钙调节和骨骼健康所必需的。我们正在建立一个新的研究模型，可以用来研究不同因素在甲状旁腺中的作用。这些因素的表征将有助于提高我们对甲状旁腺生物学及其相关疾病的了解。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15): Translational Science 15-DK-102. Develop improved animal models of NIDDK diseases. Parathyroid hormone (PTH) is one of the most important regulators of calcium and phosphate homeostasis, and of bone metabolism. FGF23, secreted from bone, is another crucial regulator of phosphate homeostasis. Recent data have suggested a bone-parathyroid axis in which FGF23 and PTH regulate each other, however, the existing data are contradictory and require clarification. Progress in understanding the molecular regulation of parathyroid cells is very slow because no cell line exists, the glands are very small, and in vivo molecular analysis is almost impossible. Since dysfunction of the parathyroid gland leads to severe consequences such as soft tissue calcification, fragile bones, chronic renal failure, myopathy, cardiac dysfunction, hematological abnormalities, rickets and osteomalacia, a new approach is needed to address this question. The overall goal of this proposal is to generate an innovative and unique mouse model with a retroviral receptor stably expressed on the surface of parathyroid cells. This mouse can then be induced to express different genes including siRNAs exclusively in the parathyroid glands through simple intraperitoneal injection of retroviral constructs. Targeting different genes alone or in combination to the parathyroids is then possible without the need to generate new transgenic mice for each construct. We will also apply this new model to a specific genetic form of hypoparathyroidism (HP). Novel heterozygous mutations in GCMB were identified in two families with a genetic, autosomal dominant form of hypoparathyroidism that have a dominant-negative effect (dnGCMB). We will express either wild type or dnGCMB in the parathyroids to identify its role in postnatal parathyroid glands. Understanding the actions of GCMB might help in the development of therapeutic agents affecting parathyroid gland function and thus could be used for a wide range of diseases, including primary hyperparathyroidism, a much more common disorder than HP, and secondary hyperparathyroidism related to chronic kidney disease. This innovative in vivo model will not only help us understand the regulatory network in the parathyroid glands but will serve as a useful model for similar research in other systems. PUBLIC HEALTH RELEVANCE: Parathyroid glands produce parathyroid hormone (PTH), which is necessary for calcium regulation and bone health. We are generating a new research model that can be used to study the role of different factors in the parathyroid gland. The characterization of these factors will help improve our understanding of parathyroid gland biology and its related diseases.