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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：
Alan S Yu
金额：
$ 31.08万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
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：
https://reporter.nih.gov/project-details/10238078
关键词：
Affect Attention Back Biological Assay Calcium Cations Colon Crystallization Data Defect Deposition Development Disease Distal Frequencies Gene Proteins Genes Genetic Polymorphism Genotype Goals Henle&apos s loop Homeostasis Human Intercellular Junctions Intestinal Secretions Intestines Ion Channel Kidney Kidney Calculi Knockout Mice Lead Limb structure Lithium Mediating Micropuncture Modeling Mus Nature Nephrocalcinosis Nephrolithiasis Papillary Pathogenesis Pathogenicity Pathway interactions Patients Permeability Phenotype Population Preparation Proteins Proximal Kidney Tubules Recording of previous events Renal tubule structure Risk Risk Factors Role Route Site Testing Thinness Tight Junctions Tissues Tracer Urinary Calculi Urine Western Blotting calcium excretion cohort conditional knockout exosome genetic variant hypercalciuria insight intestinal epithelium novel novel therapeutic intervention novel therapeutics population based protein expression radiotracer renal calcium sex thiazide urinary volunteer

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。