GCMB- Master Regulator of Parathyroid Function

GCMB-甲状旁腺功能的主调节器

基本信息

批准号：
7729158
负责人：
MICHAEL ALAN LEVINE
金额：
$ 49.54万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-20 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7729158
关键词：
Ablation Affect Alleles Biochemical Birth Blood Calcium Cell Death Cell Maintenance Cell Proliferation Cells Collaborations Data Defect Development Disease Disease of parathyroid glands Embryo Embryonic Development Endocrine System Diseases Exons Failure Gene Expression Gene Mutation Gene Targeting Genes Genetic Genetic Recombination Goals Growth Growth and Development function Health Homeostasis Human Hyperparathyroidism Hypocalcemia result Hypoparathyroidism Knowledge Laboratories Lead Left Life Longevity Maintenance Metabolic Diseases Metabolism Minerals Modeling Molecular Molecular Genetics Mus Mutant Strains Mice Mutation Neuroglia Parathyroid Hormones Parathyroid gland Patients Phenotype Pregnancy Procedures Regulation Regulator Genes Research Research Personnel Research Project Grants Role Series Serum Serum Phosphorus Level Site Techniques Terminator Codon Testing Time Transgenic Mice Transgenic Organisms Work base bone cell growth chromatin immunoprecipitation gland development human PTH protein human disease in vivo insight mouse model novel parathyroid hyperplasia postnatal precursor cell recombinase research study skeletal transcription factor

项目摘要

The long-term objective of our research is to characterize the molecular and genetic role of GCM2 in controlling parathyroid gland development during embryogenesis and parathyroid cell maintenance after birth. Studies in mice have shown that parathyroid formation is under the control of the Gcm2 gene (glial cell missing 2), which encodes a novel transcription factor that is expressed exclusively in the developing and mature parathyroid gland. Studies from our laboratory and by others have shown that genetic mutations that inactivate GCM2 in humans cause hypoparathyroidism, a metabolic disorder characterized by severe hypocalcemia and hyperphosphatemia due to deficiency of parathyroid hormone (PTH). Genetic ablation of Gcm2 in mouse embryos causes a similar phenotype with parathyroid aplasia. These observations establish GCM2 as the master control gene for embryological development of parathyroid glands, but leave unanswered questions about the role of Gcm2 during late gestation and during postnatal life. We hypothesize that expression of Gcm2 in the parathyroid is necessary throughout life to maintain parathyroid cell mass, and that lack of Gcm2 will induce parathyroid cell death. We propose to use mouse models that we have developed that enable us to genetically delete the Gcm2 gene conditionally, in a temporally and spatially controlled manner, to identify the genes that are controlled by Gcm2 action and the effect of loss of Gcm2 on growth and function of mature parathyroid cells. Mice with conditional Gcm2 alleles will also allow us to determine whether ablation of Gcm2 late in life can "rescue" mice that have parathyroid disorders that replicate the human condition primary hyperparathyroidism. The specific aims of this proposal are: 1. to characterize our mice with conditional Gcm2 alleles; 2. to determine the consequences of timed deletion of Gcm2 on parathyroid cell growth and function in normal mice and mice with parathyroid hyperplasia; and 3. to identify genes that are controlled by Gcm2, using a combination of microarray expression analysis and chromatin immunoprecipitation. Together, these experiments will elucidate the role of GCM2 in regulating parathyroid growth and development across the lifespan, and provide critical new information regarding the genes that are regulated by Gcm2. Ultimately, this information may yield new strategies for regulating parathyroid growth and/or function in patients with parathyroid disorders.

我们研究的长期目标是表征GCM2在胚胎发生过程中控制甲状旁腺发育和出生后甲状旁腺细胞维持过程中的分子和遗传作用。在小鼠中的研究表明，甲状旁腺形成在GCM2基因的控制下（神经胶质细胞缺失2），该基因编码了一种新型的转录因子，该因子仅在发育和成熟的甲状旁腺中表达。我们实验室和其他实验室的研究表明，在人类中灭活GCM2的遗传突变会引起甲状腺功能低下，这是一种因甲状旁腺激素（PTH）而导致严重低钙血症和高磷酸血症的代谢疾病。 GCM2在小鼠胚胎中的遗传消融会导致甲状旁腺染色体类似的表型。这些观察结果 GCM2是甲状旁腺的胚胎发展基因的主要控制基因，但对GCM2在妊娠后期和产后生活中的作用留下了未解决的问题。我们假设GCM2在甲状旁腺中的表达是维持甲状旁腺细胞量的必要条件，而缺乏GCM2会诱发甲状旁腺细胞死亡。我们建议使用已经开发的小鼠模型，使我们能够以时间和空间控制的方式有条件地删除GCM2基因，以识别受GCM2作用控制的基因，以及GCM2丧失对成熟甲状旁腺细胞生长和功能的影响。带有条件GCM2等位基因的小鼠还将允许我们确定GCM2的消融生命后期可以“营救”患有甲状旁腺功能障碍的小鼠，可复制人类病情原发性甲状旁腺功能亢进症。该提案的具体目的是：1。用条件GCM2等位基因表征我们的小鼠； 2。确定GCM2定时缺失对甲状旁腺增生的正常小鼠和小鼠的甲状旁腺细胞生长和功能的后果； 3。使用微阵列表达分析和染色质免疫沉淀的组合来识别由GCM2控制的基因。总之，这些实验将阐明GCM2在调节整个寿命的甲状旁腺生长和发育中的作用，并提供有关GCM2调节基因的关键新信息。最终，这些信息可能会产生新的策略，以调节甲状旁腺疾病患者的甲状旁腺增长和/或功能。