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

• 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
• 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

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.

高磷酸血症是心血管并发症（例如心血管钙化）的主要原因 患有慢性肾脏疾病（CKD）的患者。 CKD通过 两个磷激素轴，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主要通过增加近端降解来减少磷酸盐的重新吸收 小管特异性Na依赖性II磷酸转运蛋白Napi2a。尽管我们了解磷酸盐 稳态受到涉及骨骼，肠，肾脏和甲状旁腺的全身反馈回路的调节 腺体，我们认为CKD介导的磷酸盐稳态失调的开始发生在 肾。使用顺序的RNA-seq和RNAi库筛选，我们确定了一个新的候选人 磷酸盐稳态的近端小管特异性调节。此应用程序的中心前提 初步结果是1）新型近端管状特异性蛋白的调节在物理上与 NAPI2A并通过影响NAPI2A的稳定性影响磷酸盐的重新吸收，2）用这种敲除的小鼠 蛋白质因磷酸稳态而严重破坏，导致严重的高磷酸血症和 血管钙化通过肾刷板膜中的NAPI2A大幅增加，3）CKD 显着降低了肾刷寄宿膜中该蛋白质的水平。这个项目是一个合作 患有心血管疾病生物学的专家（Miyazaki，PhD科学家）和磷酸盐之间 运输商（Blaine，MD/PhD科学家）。我们将采用创新的新型微观方法论 和新型的遗传小鼠模型，以评估新型小管特异性蛋白在调节中的作用 磷酸盐稳态以及CKD介导的高磷酸血症和血管的发病机理 钙化。提出了两个具体目标。 AIM 1将确定近端管状的机制 特异性蛋白质会根据PTH和FGF23的响应来调节NAPI2A降解。 AIM 2将检查是否 近端管状特异性蛋白有助于CKD介导的高磷酸血症和心血管 完成。该项目的完成将为CKD介导的高磷酸血症和 心血管并发症。