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

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

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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:
    $ 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
  • 批准号:
    8152114
  • 财政年份:
    2010
  • 资助金额:
    $ 31.08万
  • 项目类别:

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