Role of claudin-2 in Calcium Homeostasis and Kidney Stone Disease
Claudin-2 在钙稳态和肾结石疾病中的作用
基本信息
- 批准号:10238078
- 负责人:
- 金额:$ 31.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-18 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAttentionBackBiological AssayCalciumCationsColonCrystallizationDataDefectDepositionDevelopmentDiseaseDistalFrequenciesGene ProteinsGenesGenetic PolymorphismGenotypeGoalsHenle&aposs loopHomeostasisHumanIntercellular JunctionsIntestinal SecretionsIntestinesIon ChannelKidneyKidney CalculiKnockout MiceLeadLimb structureLithiumMediatingMicropunctureModelingMusNatureNephrocalcinosisNephrolithiasisPapillaryPathogenesisPathogenicityPathway interactionsPatientsPermeabilityPhenotypePopulationPreparationProteinsProximal Kidney TubulesRecording of previous eventsRenal tubule structureRiskRisk FactorsRoleRouteSiteTestingThinnessTight JunctionsTissuesTracerUrinary CalculiUrineWestern Blottingcalcium excretioncohortconditional knockoutexosomegenetic varianthypercalciuriainsightintestinal epitheliumnovelnovel therapeutic interventionnovel therapeuticspopulation basedprotein expressionradiotracerrenal calciumsexthiazideurinaryvolunteer
项目摘要
PROJECT SUMMARY/ABSTRACT
Kidney stones affect 9% of the population and idiopathic hypercalciuria is the major pathogenic risk factor. Our
long-term goal is to elucidate the pathogenesis of idiopathic hypercalciuria and develop novel therapies. The
renal proximal tubule reabsorbs 70% of filtered calcium, which is believed to occur via the paracellular pathway.
Claudin-2 is a paracellular cation channel that is expressed in the proximal renal tubule and in intestinal
epithelium. In preliminary studies, we show that claudin-2 knockout mice have renal and absorptive
hypercalciuria, leading to severe papillary nephrocalcinosis. Moreover, we find that claudin-2 gene variants are
associated with kidney stone disease in humans. We hypothesize that claudin-2 mediates calcium reabsorption
in the proximal tubule and calcium secretion in the colon. Loss of claudin-2 increases calcium delivery to the
loop of Henle, and predisposes to inner medullary calcium deposition and hence kidney stone disease. The
specific aims to test this hypothesis are: (1) Test whether claudin-2 mediates paracellular calcium reabsorption
in the renal proximal tubule. We will use tubule micropuncture of claudin-2 global knockout mice, determine the
contribution of the proximal tubule with kidney-specific conditional knockout mice, test the role of claudin-2 in the
hypocalciuric effect of thiazides, and explore the effect of sex. (2) Test whether claudin-2 mediates intestinal
secretion of calcium. We will generate intestine-specific claudin-2 knockout mice and perform tracer flux assays
in everted intestinal sacs and Ussing chamber preparations. (3) Test whether human claudin-2 gene variants
and protein expression are associated with urine calcium and kidney stones. We will conduct a gene association
study in 3 U.S. population-based cohorts to test the association of claudin-2 gene polymorphisms with a history
of kidney stones and calcium excretion. In a separate cohort of kidney stone formers and matched normal
volunteers, we will test the association of claudin-2 protein abundance in urinary exosomes with hypercalciuric
kidney stone disease.
项目总结/文摘
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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Alan S Yu其他文献
Alan S Yu的其他文献
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{{ truncateString('Alan S Yu', 18)}}的其他基金
Biomedical Research Core 3 - Clinical Research Core
生物医学研究核心 3 - 临床研究核心
- 批准号:
10475048 - 财政年份:2020
- 资助金额:
$ 31.08万 - 项目类别:
Biomedical Research Core 3 - Clinical Research Core
生物医学研究核心 3 - 临床研究核心
- 批准号:
10059768 - 财政年份:2020
- 资助金额:
$ 31.08万 - 项目类别:
Biomedical Research Core 3 - Clinical Research Core
生物医学研究核心 3 - 临床研究核心
- 批准号:
10214616 - 财政年份:2020
- 资助金额:
$ 31.08万 - 项目类别:
Biomedical Research Core 3 - Clinical Research Core
生物医学研究核心 3 - 临床研究核心
- 批准号:
10686076 - 财政年份:2020
- 资助金额:
$ 31.08万 - 项目类别:
Role of claudin-2 in Calcium Homeostasis and Kidney Stone Disease
Claudin-2 在钙稳态和肾结石疾病中的作用
- 批准号:
10020951 - 财政年份:2019
- 资助金额:
$ 31.08万 - 项目类别:
Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) IV: Prognosis for End-Stage Renal Disease and Biomarker Validation
多囊肾病放射影像研究联盟 (CRISP) IV:终末期肾病的预后和生物标志物验证
- 批准号:
9906761 - 财政年份:2017
- 资助金额:
$ 31.08万 - 项目类别:
CRISP III - Kansas Polycystic Kidney Imaging Program Supplemental Request
CRISP III - 堪萨斯州多囊肾成像计划补充请求
- 批准号:
9269449 - 财政年份:2016
- 资助金额:
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Randomized, controlled pilot study of nicotinamide in polycystic kidney disease
烟酰胺治疗多囊肾病的随机对照试验研究
- 批准号:
8807460 - 财政年份:2015
- 资助金额:
$ 31.08万 - 项目类别:
Randomized, controlled pilot study of nicotinamide in polycystic kidney disease
烟酰胺治疗多囊肾病的随机对照初步研究
- 批准号:
9136856 - 财政年份:2015
- 资助金额:
$ 31.08万 - 项目类别:
Structure-Function Studies of Tight Junction Membrane Proteins
紧密连接膜蛋白的结构-功能研究
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8152114 - 财政年份:2010
- 资助金额:
$ 31.08万 - 项目类别:
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