The Regulation of the Parathyroid Gland

描述（由申请人提供）：本申请提出了在慢性肾病（CKD）背景下对甲状旁腺的创新研究。 CKD 是世界范围内的一个主要健康问题，具有临床相关性的新数据对于开发治疗这种涉及甲状旁腺疾病的严重并发症的新方法至关重要。 CKD 是一种复杂的疾病，始于肾功能退化，发展至终末期时，其特点是出现多种系统性问题。最严重的全身问题与矿物质和激素失衡有关，引发继发性甲状旁腺功能亢进并伴有甲状旁腺增生，这是 CKD 患者发病和死亡的最重要原因。导致增生的监管控制崩溃的机制尚不完全清楚。我们提出了两个研究目标，旨在扩大对这一严重医学问题的理解。我们的首要目标是更全面地了解 Klotho 在甲状旁腺中表达的作用。 Klotho 在甲状旁腺中表达，并已被证明可以通过充当 FGF23（磷酸盐稳态的关键调节剂）的辅助因子来调节 PTH 的产生。我们有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踪我们首次对小鼠甲状旁腺进行微阵列分析时生成的数据。我们的分析发现了一些以前未曾报道或研究过的基因在增生性腺体中的表达。我们选择了一个基因 Fgfr2 作为进一步研究的高度关注靶点，以确定其在增生诱导和进展中的作用。我们将利用从小鼠甲状旁腺中分离总 mRNA 的创新技术，结合我们的转基因小鼠模型，研究该基因在增生的发展和维持中的作用和机制，并确定该过程中的关键伙伴基因。鉴于 CKD 的严重医疗和经济影响，我们期望生成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.