The Regulation of the Parathyroid Gland

甲状旁腺的调节

• 批准号: 8416194
• 负责人: BEATE LANSKE - MANNSTADT
• 金额: $ 55.12万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416194
• 关键词: Address; Adult; Affect; Applications Grants; Bone Diseases; Calcium; Calcium-Sensing Receptors; Candidate Disease Gene; Cardiovascular Diseases; Cell Proliferation; Cells; Chronic Kidney Failure; Clinical; Complex; Complication; Data; Development; Dialysis procedure; Diet; Disease; Down-Regulation; Equilibrium; FGFR2 gene; Gene Expression; Gene Expression Profile; Genes; Gland; Health; Healthcare; Homeostasis; Hormonal; Hormones; Hyperplasia; In Vitro; Incidence; Investigation; Knockout Mice; Lead; Maintenance; Medical; Medical Economics; Messenger RNA; Methods; Microarray Analysis; Minerals; Morbidity - disease rate; Mus; Operative Surgical Procedures; Outcome; Parathyroid gland; Patients; Phosphorus; Physiologic calcification; Physiological; Population; Prevention; Process; Production; Public Health; Regulation; Renal Osteodystrophy; Renal function; Reporting; Research; Role; Secondary Hyperparathyroidism; Serum; Serum Calcium Level; Staging; Techniques; Time; Transgenic Mice; Treatment Efficacy; United States; Vitamin D; Work; aging population; analog; base; bone; calcification; calcium phosphate; clinically relevant; cost; fibroblast growth factor 23; improved; in vitro Model; in vivo; innovation; inorganic phosphate; interest; mortality; mouse model; novel; receptor; response; skeletal

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.

描述（由申请人提供）：本申请提出慢性肾脏疾病（CKD）背景下甲状旁腺的创新研究。慢性肾病是一个主要的、全球性的健康问题，具有临床相关性的新数据对于开发治疗这种疾病累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，以肾功能退化开始，并以多种系统性问题为特征，发展到终末期。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。导致增生的调节控制失效的机制仅部分被理解。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在甲状旁腺中表达的Klotho的作用。Klotho在甲状旁腺中表达，并已被证明通过作为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。我们有新的初步数据，首次表明Klotho可能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从小鼠甲状旁腺的首次微阵列分析中产生的数据。我们的分析发现了一些基因在增生性腺体中的表达，这些基因以前没有被报道或研究过。我们选择了一个基因Fgfr2作为进一步研究的高兴趣靶点，以确定其在增生的诱导和进展中的作用。我们将利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CKD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。