The Pathobiology of Nephrolithiasis

描述（由申请人提供）：肾结石是一种常见的，昂贵的和复发性的条件，但有稀疏的遗传因素和基因-环境相互作用的影响的信息。该计划项目的总体长期目标是扩大我们对影响肾结石形成总体风险的生理过程，遗传易感性和基因-环境相互作用的了解，以制定最佳预防策略。项目1和项目2关注控制肾钙、草酸盐和柠檬酸盐排泄的基本生理问题，这对草酸钙结石形成至关重要。具体而言，项目1将研究关键草酸盐和柠檬酸盐转运蛋白的生理作用和调节。项目2将有助于完善我们对钙敏感受体的肾脏生理作用的理解，钙敏感受体作为钙、水和盐沿肾单位沿着转运的关键调节位点发挥作用。项目1和2中生理学研究的基因以及其他重要候选基因的遗传变异谱将在核心A（遗传学核心）的帮助下确定。然后，项目3将研究遗传变异的影响（使用全基因组关联研究）及其与饮食的相互作用对3000名具有和不具有历史结石形成的良好表型参与者的24小时尿液组成的影响，建立在该项目可用的独特资源和专业知识的基础上。最后，非同义编码SNP的功能效应将在项目1和2中进行研究;这将有助于将项目3的重点放在遗传变异性与功能后果上，也将有助于定义项目3中发现的遗传关联的生理基础。通过从各种方法研究这种复杂的疾病，从基本生理学到尿液成分，这个项目将大大提高我们对肾结石病理生物学的理解，研究结果将具有直接的临床应用。

DESCRIPTION (provided by applicant): Nephrolithiasis is a common, costly and recurrent condition, but there is sparse information on the influence of genetic factors and gene-environment interactions. The overall long-term objective of this Program Project is to expand our knowledge of the physiologic processes, genetic predisposition, and gene-environment interactions that affect the overall risk of kidney stone formation in order to formulate optimal preventive strategies. Projects 1 and 2 focus on basic physiological issues in the control of renal calcium, oxalate, and citrate excretion, which are critical for calcium oxalate stone formation. Specifically, the physiological role and regulation of key oxalate and citrate transporters will be studied in Project 1. Project 2 will serve to refine our understanding of the renal physiological role of the calcium sensing receptor, which functions as a key regulatory locus for calcium, water, and salt transport all along the nephron. The spectrum of genetic variation in the genes under physiological study in Projects 1 and 2 as well as other important candidate genes will be determined with the aid of Core A, the genetics Core. Project 3 will then examine the impact of genetic variation (using genome wide association studies) and its interaction with diet on 24 hour urine composition in 3000 well-phenotyped participants with and without a history stone formation, building on the unique resources and expertise available for this project. Finally, the functional effect of non-synonymous coding SNPs will be studied in Projects 1 and 2; this will help to focus Project 3 on genetic variability with functional consequences and will also help define the physiological underpinnings of the genetic associations found in Project 3. By studying this complex disease from a variety of approaches, ranging from basic physiology to urine composition, this Program Project will greatly enhance our understanding of the pathobiology of nephrolithiasis and the findings will have direct clinical application.