Proximal Tubule Transport Defect in Hyp Mice
Hyp 小鼠的近端小管运输缺陷
基本信息
- 批准号:6863584
- 负责人:
- 金额:$ 23.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-03-01 至 2008-02-29
- 项目状态:已结题
- 来源:
- 关键词:brush border membraneenzyme activityfibroblast growth factorgenetically modified animalshypophosphatemiaindomethacinkidney disorder chemotherapykidney pharmacologylaboratory mouselaboratory rabbitmitogen activated protein kinaseosteomalaciapolymerase chain reactionprostaglandin Eprotein kinase Crenal tubular transportrenal tubulericketsvitamin D deficiencyvitamin D resistant rickets
项目摘要
DESCRIPTION (provided by applicant): X-linked hypophosphatemia is characterized by renal phosphate wasting resulting in hypophosphatemia, and a relative deficiency of 1,25(OH)2 vitamin D. These defects are thought to be due to increased levels of a circulating phosphatonin, FGF-23. Current therapy includes administration of oral phosphate and 1,25(OH)2 vitamin D which results in improvement of rickets but can result in hyperparathyroidism, hypercalcemia, hypercalciuria and nephrocalcinosis. We have found that the Hyp mouse, which has the same genetic defect as humans with X-linked hypophosphatemia, has a higher rate of urinary prostaglandin excretion and proximal tubule PGE2 content than C57/B6 mice. Indomethacin administration in vivo and in vitro totally normalizes the hyperphosphaturia, the transport defect in isolated perfused tubules and NaPi co-transporter abundance in brush border membrane vesicles. In addition we find that the phosphate transport defect and the paucity of NaPi transporters in Hyp mice are reversible within an hour of incubation in vitro suggesting rapid phosphatonin washout. We demonstrate that luminal addition of FGF-23 inhibits phosphate transport in the mouse and rabbit proximal tubule. The first Aim of this proposal is to characterize how the putative phosphatonin, FGF-23, inhibits phosphate transport in isolated perfused mouse proximal tubules. The second Aim is to determine the role of PGE2 in the regulation of proximal tubule phosphate transport in X-linked hypophosphatemia. The third Aim is to determine the role of abnormal prostaglandin production in the pathogenesis of the bone and renal abnormalities in Hyp mice. We will examine if chronic indomethacin therapy, which we find increases serum phosphate in Hyp mice, improves their bone disease, growth and abnormal vitamin D metabolism. These studies will not only examine the pathogenesis of this disorder, but will directly examine if indomethacin potentially represents a novel therapy for this disease.
描述(由申请方提供):X连锁低磷酸盐血症的特征是肾性磷酸盐消耗导致低磷酸盐血症和1,25(OH)2维生素D相对缺乏。这些缺陷被认为是由于循环磷酸激素FGF-23水平增加所致。目前的治疗包括口服磷酸盐和1,25(OH)2维生素D,这导致佝偻病的改善,但可能导致甲状旁腺功能亢进、高钙血症、高钙尿症和肾钙质沉着症。我们已经发现,Hyp小鼠,这与人类具有相同的遗传缺陷与X-连锁低磷酸盐血症,具有较高的尿前列腺素排泄率和近端小管PGE 2含量比C57/B6小鼠。吲哚美辛给药在体内和体外完全正常化的高磷酸尿症,运输缺陷,在孤立的灌流小管和刷状缘膜囊泡中的NaPi共转运丰度。此外,我们发现Hyp小鼠中磷酸盐转运缺陷和NaPi转运蛋白的缺乏在体外孵育一小时内是可逆的,这表明快速的磷酸激素洗脱。我们证明,腔添加FGF-23抑制磷酸盐转运在小鼠和兔近端小管。本建议的第一个目的是表征假定的磷酸激素,FGF-23,抑制磷酸盐转运在离体灌注小鼠近端小管。第二个目的是确定PGE 2在X连锁低磷血症近端小管磷酸盐转运调节中的作用。第三个目的是确定异常前列腺素产生在Hyp小鼠骨和肾异常发病机制中的作用。我们将研究慢性吲哚美辛治疗,我们发现增加血清磷酸盐在Hyp小鼠,改善他们的骨骼疾病,生长和异常的维生素D代谢。这些研究不仅将检查这种疾病的发病机制,而且将直接检查吲哚美辛是否可能代表这种疾病的新疗法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MICHEL GERARD BAUM其他文献
MICHEL GERARD BAUM的其他文献
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{{ truncateString('MICHEL GERARD BAUM', 18)}}的其他基金
Effect of Prenatal Programming on Renal Tubular Transport
产前规划对肾小管运输的影响
- 批准号:
7707197 - 财政年份:2009
- 资助金额:
$ 23.4万 - 项目类别:
Effect of Prenatal Programming on Renal Tubular Transport
产前规划对肾小管运输的影响
- 批准号:
8136968 - 财政年份:2009
- 资助金额:
$ 23.4万 - 项目类别:
Effect of Prenatal Programming on Renal Tubular Transport
产前规划对肾小管运输的影响
- 批准号:
8319557 - 财政年份:2009
- 资助金额:
$ 23.4万 - 项目类别:
Effect of Prenatal Programming on Renal Tubular Transport
产前规划对肾小管运输的影响
- 批准号:
7920179 - 财政年份:2009
- 资助金额:
$ 23.4万 - 项目类别:
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