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

研究甲状旁腺的创新小鼠模型及其在人类疾病中的应用

• 批准号: 7934573
• 负责人: BEATE LANSKE - MANNSTADT
• 金额: $ 49.37万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-19 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7934573
• 关键词: Address; Affect; Animal Model; Area; Attention; Biology; Birds; Calcium; Cardiac; Cardiovascular system; Cell Line; Cells; Chronic Kidney Failure; Clinical; Data; Development; Disease; Dominant-Negative Mutation; Effectiveness; Energy Metabolism; Family; Functional disorder; Gene Expression; Gene Mutation; Gene Targeting; Generations; Genes; Genetic; Gland; Goals; Growth and Development function; Homeostasis; Hyperparathyroidism; Hypoparathyroidism; Injection of therapeutic agent; Intraperitoneal Injections; Ions; Life; Maintenance; Minerals; Modeling; Molecular; Molecular Analysis; Mus; Mutation; Myopathy; National Institute of Diabetes and Digestive and Kidney Diseases; Osteomalacia; Parathyroid Hormones; Parathyroid gland; Physiologic calcification; Physiological; Process; Regulation; Research; Research Personnel; Retroviral Vector; Rickets; Role; Secondary Hyperparathyroidism; Signal Transduction; Specificity; Surface; System; Therapeutic Agents; Time; Tissues; Transgenes; Transgenic Mice; Translational Research; Tva receptor; Up-Regulation; bone; bone health; bone metabolism; calcification; calcium phosphate; human PTH protein; human disease; improved; in vivo; in vivo Model; innovation; inorganic phosphate; knock-down; mortality; mouse model; mutant; novel; novel strategies; postnatal; promoter; public health relevance; receptor; skeletal; soft tissue; transcription factor

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.

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）：转化科学15- dk -102。开发改进的NIDDK疾病动物模型。甲状旁腺激素（PTH）是钙和磷酸盐稳态和骨代谢最重要的调节因子之一。骨分泌的FGF23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，但现有的数据相互矛盾，需要澄清。了解甲状旁腺细胞分子调控的进展非常缓慢，因为没有细胞系存在，腺体非常小，体内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、心功能障碍、血液学异常、佝偻病和骨软化等严重后果，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具有在甲状旁腺细胞表面稳定表达逆转录病毒受体的创新和独特的小鼠模型。然后，通过简单的腹腔注射逆转录病毒构建物，可以诱导这只小鼠在甲状旁腺中表达不同的基因，包括sirna。针对不同的基因单独或组合到甲状旁腺是可能的，而不需要为每个构建产生新的转基因小鼠。我们还将把这个新模型应用于甲状旁腺功能减退症（HP）的特定遗传形式。在两个家族中发现了一种新的杂合突变，具有显性-负显性效应的常染色体显性甲状旁腺功能低下（dnGCMB）。我们将在甲状旁腺中表达野生型或ngcmb，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药物，因此可用于广泛的疾病，包括原发性甲状旁腺功能亢进（一种比HP更常见的疾病）和与慢性肾脏疾病相关的继发性甲状旁腺功能亢进。这种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。