The Pathobiology of Nephrolithiasis

描述(申请人提供)：肾结石是一种常见的、昂贵的和反复发作的疾病，但关于遗传因素和基因-环境相互作用的影响的信息很少。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，以便制定最佳的预防策略。项目1和2集中在控制肾脏钙、草酸和柠檬酸排泄的基本生理问题上，这些都是草酸钙结石形成的关键。具体来说，项目1将研究关键的草酸和柠檬酸转运蛋白的生理作用和调节。项目2将有助于加深我们对钙感应受体在肾脏的生理作用的理解，它是钙、水和盐沿肾单位运输的关键调节点。项目1和2中正在进行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遗传学核心核心A的帮助下确定。然后，项目3将基于该项目可用的独特资源和专业知识，研究遗传变异(使用全基因组关联研究)及其与饮食的相互作用对3000名有和没有结石形成历史的表型良好的参与者24小时尿液成分的影响。最后，非同义编码SNPs的功能效应将在项目1和2中进行研究；这将有助于项目3将重点放在具有功能后果的遗传变异性上，并将有助于定义项目3中发现的遗传关联的生理基础。通过从基本生理学到尿液成分等各种方法研究这种复杂的疾病，该项目将极大地增强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.