A Novel Driver of Hyperphosphatemia and Vascular Calcification in CKD

CKD 中高磷血症和血管钙化的新驱动因素

基本信息

批准号：
10546434
负责人：
JUDITH T., BLAINE
金额：
$ 48.86万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10546434
关键词：
Affect Apical Binding Biology Brush Border Cardiovascular Diseases Cardiovascular system Cause of Death Cells Chronic Kidney Failure Clinical Research Collaborations Custom Data Disease Doctor of Philosophy End stage renal failure Equilibrium Etiology Event Excision Feedback Fluorescence Fluorescence Microscopy Fluorescence Resonance Energy Transfer Functional disorder Genes Genetic Heart Hypertrophy Homeostasis Hormonal Human Image In Vitro Inorganic Phosphate Transporter Intestines Kidney Knock-out Knockout Mice Libraries Mediating Membrane Methodology Microscopic Modeling Molecular Mus Myocardial dysfunction PTH gene Parathyroid gland Pathogenesis Patients Proteins Proximal Kidney Tubules RNA Interference Regulation Reporting Resistance Role Scheme Scientist Signal Transduction Small Interfering RNA Sodium Spectrum Analysis Testing Tubular formation Ultrafiltration Urine Vascular calcification Work absorption bone brush border membrane calcification cellular microvillus fibroblast growth factor 23 in vivo innovation inorganic phosphate insight mRNA sequencing mortality mouse model novel reconstitution response screening sodium-hydrogen exchanger regulatory factor transcriptome sequencing uptake

项目摘要

Hyperphosphatemia is a major cause of cardiovascular complications such as cardiovascular calcification in patients with chronic kidney disease (CKD). CKD causes a severe imbalance of phosphate homeostasis through the disruption of two phosphaturic hormonal axes, parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23). PTH and FGF-23 reduce phosphate re-absorption mainly by increasing degradation of a proximal tubule-specific Na-dependent type II phosphate transporter, NaPi2a. Although we understand that phosphate homeostasis is regulated by a systemic feedback loop involving the bone, intestine, kidneys and parathyroid gland, we believe that the initiation of CKD-mediated dysregulation of phosphate homeostasis occurs at the kidney. Using a sequential RNA-seq and RNAi library screening, we have identified a novel candidate for proximal tubule-specific regulation of phosphate homeostasis. The central premise of this application from our preliminary results is that 1) the modulation of a novel proximal tubular-specific protein physically interacts with NaPi2a and affects phosphate re-absorption by affecting NaPi2a stability, 2) the mice with a knockout of this protein developed severe disruption of phosphate homeostasis, resulting in severe hyperphosphatemia and vascular calcification by drastically increasing NaPi2a in the renal brush boarder membrane and 3) CKD significantly reduces levels of this protein in the renal brush boarder membrane. This project is a collaboration between experts with the biology of cardiovascular diseases (Miyazaki, PhD scientist) and phosphate transporters (Blaine, MD/PhD scientist). We will employ an innovative panel of novel microscopic methodologies and novel genetic mouse models to assess the role of the novel proximal tubule-specific protein in the regulation of phosphate homeostasis and the pathogenesis of CKD-mediated hyperphosphatemia and vascular calcification. Two specific aims are proposed. Aim 1 will identify mechanisms by which the proximal tubular- specific protein regulates NaPi2a degradation in response to PTH and FGF23. Aim 2 will examine whether the proximal tubular-specific protein contributes to CKD-mediated hyperphosphatemia and cardiovascular completions. Completion of this project will provide a novel target of CKD-mediated hyperphosphatemia and cardiovascular complications.

高磷血症是心血管并发症的主要原因，例如心血管钙化患有慢性肾脏病（CKD）的患者。 CKD 通过以下方式导致磷酸盐稳态严重失衡两条磷酸盐激素轴、甲状旁腺激素 (PTH) 和成纤维细胞生长因子 23 的破坏（FGF-23）。 PTH 和 FGF-23 主要通过增加近端磷酸盐的降解来减少磷酸盐重吸收肾小管特异性 Na 依赖性 II 型磷酸盐转运蛋白 NaPi2a。虽然我们知道磷酸盐体内平衡由涉及骨、肠、肾脏和甲状旁腺的系统反馈回路调节腺体，我们认为 CKD 介导的磷酸盐稳态失调的起始发生在肾。通过连续的 RNA-seq 和 RNAi 文库筛选，我们已经确定了一种新的候选物磷酸盐稳态的近端小管特异性调节。这个应用程序的中心前提来自我们初步结果是 1) 一种新型近端肾小管特异性蛋白的调节与 NaPi2a 并通过影响 NaPi2a 稳定性来影响磷酸盐重吸收，2) 敲除该基因的小鼠蛋白质严重破坏磷酸盐稳态，导致严重的高磷血症和肾刷缘膜中 NaPi2a 急剧增加导致血管钙化和 3) CKD 显着降低肾刷缘膜中这种蛋白质的水平。这个项目是一个合作项目心血管疾病生物学专家（宫崎博士科学家）和磷酸盐之间转运蛋白（布莱恩，医学博士/博士科学家）。我们将采用新颖的微观方法的创新小组和新的遗传小鼠模型，以评估新的近端小管特异性蛋白在调节中的作用磷酸盐稳态的影响以及 CKD 介导的高磷酸盐血症和血管性的发病机制钙化。提出了两个具体目标。目标 1 将确定近端肾小管的机制特定蛋白响应 PTH 和 FGF23 调节 NaPi2a 降解。目标 2 将检查是否近端肾小管特异性蛋白导致 CKD 介导的高磷血症和心血管疾病完成情况。该项目的完成将为 CKD 介导的高磷血症和心血管并发症。