GCMB- Master Regulator of Parathyroid Function

我们研究的长期目标是确定GCM2在控制甲状旁腺胚胎发育和甲状旁腺细胞出生后维持过程中的分子和遗传学作用。对小鼠的研究表明，甲状旁腺的形成受Gcm2基因(胶质细胞缺失2)的控制，该基因编码一种新的转录因子，仅在发育和成熟的甲状旁腺中表达。我们实验室和其他人的研究表明，在人类中GCM2失活的基因突变会导致甲状旁腺功能减退，这是一种代谢紊乱，其特征是由于甲状旁腺激素(PTH)缺乏而导致严重的低钙血症和高磷血症。小鼠胚胎中Gcm2的遗传消融导致与甲状旁腺再生障碍性贫血相似的表型。这些观察结果证明 Gcm2是甲状旁腺胚胎发育的主控基因，但Gcm2在妊娠晚期和出生后生命中的作用尚无定论。我们假设Gcm2在甲状旁腺中的表达是维持甲状旁腺细胞团的生命所必需的，并且缺乏Gcm2会导致甲状旁腺细胞死亡。我们建议使用我们建立的小鼠模型，使我们能够以时间和空间控制的方式有条件地从基因上删除Gcm2基因，以确定受Gcm2作用控制的基因以及Gcm2缺失对成熟甲状旁腺细胞生长和功能的影响。携带条件性Gcm2等位基因的小鼠也将允许我们确定是否消融Gcm2 在晚年可以“拯救”患有甲状旁腺疾病的小鼠，这种疾病复制了人类的甲状旁腺机能亢进症。这项建议的具体目的是：1.确定我们的小鼠具有条件性Gcm2等位基因；2.确定Gcm2定时缺失对正常小鼠和甲状旁腺增生小鼠甲状旁腺细胞生长和功能的影响；以及3.结合微阵列表达分析和染色质免疫沉淀，识别受Gcm2调控的基因。总之，这些实验将阐明GCM2在调节甲状旁腺生长发育中的作用，并提供关于Gcm2调控基因的关键新信息。最终，这些信息可能会产生新的策略来调节甲状旁腺疾病患者的甲状旁腺生长和/或功能。

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.