The Regulation of the Parathyroid Gland

描述（由申请人提供）：本申请提出了在慢性肾脏疾病（CKD）背景下对甲状旁腺进行的创新研究。CKD是一个主要的全球性健康问题，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。CKD是一种复杂的疾病，其开始于肾功能的退化，并且随着其进展到其终末期，其特征在于多种系统性问题。最严重的全身性问题与矿物质和激素失衡有关，这些失衡引发继发性甲状旁腺功能亢进伴甲状旁腺增生，这是CKD患者发病率和死亡率的最重要原因。导致增生的调节控制的崩溃的潜在机制仅被部分理解。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。我们的第一个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，并已显示通过充当FGF 23的辅因子来调节PTH产生，FGF 23是磷酸盐稳态的关键调节剂。我们有新的初步数据，首次表明Klotho可能具有调节血清钙变化反应的额外作用。我们的第二个目标是追踪我们从第一次小鼠甲状旁腺微阵列分析中获得的数据。我们的分析发现了一些基因的表达在增生的腺体，没有报道或以前的研究。我们已经选择了一个基因，Fgfr 2，作为进一步研究的高度兴趣的目标，以确定其在增生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，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的严重医学和经济影响，我们预期生成的数据具有高度临床相关性。 公共卫生相关性：甲状旁腺产生甲状旁腺激素以响应低血清钙以维持矿物质稳态，但由于其体积小且缺乏任何体外模型，因此仅可能对其功能进行有限的研究。慢性肾衰竭患者发生继发性甲状旁腺功能亢进，其与肾性骨营养不良、骨骼外钙化、骨矿化问题和心血管疾病相关，因此是CKD患者发病的主要因素。我们提出的研究使用新技术来调查甲状旁腺增生和SHPT发展的原因。

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. PUBLIC HEALTH RELEVANCE: The parathyroid gland produces parathyroid hormone in response to low serum calcium to maintain mineral homeostasis, but due to its small size and the lack of any in vitro models only limited studies of its function are possible. Patients with chronic kidney failure develop secondary hyperparathyroidism which is associated with renal osteodystrophy, extra-skeletal calcification, bone mineralization problems and cardiovascular disease and is thus a major factor in morbidity in CKD patients. Our proposed research uses novel techniques to investigate the causes for the development of parathyroid gland hyperplasia and SHPT.