The Regulation of the Parathyroid Gland

描述(由申请人提供)：该申请提出了在慢性肾脏疾病(CKD)的背景下甲状旁腺的创新研究。慢性肾脏病是一个主要的、世界范围的健康问题，具有临床相关性的新数据对于开发治疗这种疾病涉及甲状旁腺的严重并发症的新方法至关重要。慢性肾脏病是一种复杂的疾病，始于肾功能的退化，其特征是在进展到终末期时出现大量的全身问题。最严重的全身问题与矿物质和激素失衡有关，继发性甲状旁腺功能亢进伴随甲状旁腺增生，这是CKD患者发病率和死亡率的最重要原因。人们对导致增生的监管控制崩溃的机制只有部分了解。我们提出了两个研究目标，试图扩大对这一严重医学问题的理解。我们的第一个目标是对Klotho在甲状旁腺中表达的作用有一个更全面的了解。Klotho在甲状旁腺中表达，并被证明通过作为FGF23的辅助因子来调节PTH的产生，FGF23是磷酸盐稳态的关键调节因子。我们有了新的初步数据，首次表明Klotho可能具有调节对血清钙变化的反应的额外作用。我们的第二个目标是追求我们首次对小鼠甲状旁腺进行微阵列分析所产生的数据。我们的分析发现了一些基因在增生性腺体中的表达，这些基因以前没有报道或研究过。我们选择了一个基因，FGFR2，作为一个高度感兴趣的靶点进行进一步的研究，以确定它在增生性疾病的诱导和进展中的作用。我们将使用我们的创新技术从小鼠甲状旁腺中分离总mRNA，并结合我们的转基因小鼠模型来研究该基因在增生的发生和维持中的作用和机制，并确定这一过程中的关键伙伴基因。考虑到慢性肾脏病严重的医疗和经济影响，我们期望产生的数据具有很高的临床相关性。

DESCRIPTION (provided by applicant): This application proposes innovative studies of the parathyroid gland in the context of chronic kidney disease (CKD). CKD is a major, world-wide health concern and new data with clinical relevance are critical to developing new methods for treatment of the serious complications of this disease that involve the parathyroid gland. CKD is a complex disease that begins with degradation in kidney function and is characterized by a multitude of systemic problems as it progresses to its end stages. The most severe systemic problems are related to the mineral and hormonal imbalances that instigate secondary hyperparathyroidism accompanied by parathyroid gland hyperplasia, which is the most significant cause of morbidity and mortality in CKD patients. The mechanisms underlying the breakdown in regulatory controls that lead to hyperplasia are only partially understood. We propose two research aims that seek to expand the understanding of this serious medical issue. Our first aim is to develop a more comprehensive understanding of the role for Klotho that is expressed in the parathyroids. Klotho is expressed in the parathyroid gland and has been shown to regulate PTH production by acting as co-factor for FGF23, a key regulator of phosphate homeostasis. We have novel preliminary data that show for the first time that Klotho may have an additional role of modulating the response to changes in serum calcium. Our second aim is to pursue data we generated from the first ever microarray analysis of mouse parathyroid glands. Our analysis has discovered the expression of some genes in hyperplasic glands that have not been reported or studied previously. We have selected one gene, Fgfr2, as a high interest target for further study to determine its role in the induction and progression of hyperplasia. We will use our innovative technique for isolating total mRNA from mouse parathyroid glands in combination with our transgenic mouse models to study the role and mechanisms of this gene in the development and maintenance of hyperplasia and to identify key partner genes in this process. The data we expect to generate is of high clinical relevance given the serious medical and economic effects of CKD.