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.
项目摘要/摘要
肾结石影响了9%的人口,而特发性高钙尿是主要的致病风险因素。我们的
长期目标是阐明特发性高钙尿的发病机制,并开发新的治疗方法。这个
肾近端小管重吸收70%过滤后的钙,这被认为是通过细胞旁途径发生的。
Claudin-2是一种细胞旁阳离子通道,表达于近端肾小管和肠道。
上皮组织。在初步研究中,我们发现claudin-2基因敲除小鼠有肾脏和吸收能力。
高钙尿,导致严重的乳头状肾钙质沉着症。此外,我们发现claudin-2基因变体是
与人类肾结石疾病有关。我们假设claudin-2介导了钙的重吸收
在近端小管和结肠的钙分泌。Claudin-2的丢失增加了钙向细胞的输送
亨勒环,易发生内髓内钙沉积,从而导致肾结石。这个
检验这一假说的具体目的是:(1)检验claudin-2是否介导细胞旁钙重吸收
在肾近端小管中。我们将使用claudin-2全局基因敲除小鼠的肾小管微穿刺法,确定
肾脏特异性条件性基因敲除小鼠近端小管的作用,测试claudin-2在
降钙作用的硫氮化物,并探讨性别的影响。(2)检测claudin-2对肠道的调节作用
钙的分泌。我们将产生肠道特异的claudin-2基因敲除小鼠,并进行示踪剂通量分析
在外翻的肠囊和Ussing小室制剂中。(3)检测人类claudin-2基因变异
和蛋白的表达与尿钙和肾结石有关。我们将进行基因关联
在3个美国人群队列中研究claudin-2基因多态与病史的关系
肾结石和钙的排泄。在肾结石患者和匹配的正常肾结石患者的单独队列中
志愿者,我们将测试尿外切体中Claudin-2蛋白丰度与高钙尿症的关系
肾结石。
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:
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:
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:
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:
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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
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9269449 - 财政年份:2016
- 资助金额:
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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
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9136856 - 财政年份:2015
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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:
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