MENTORED PATIENT-ORIENTED RESEARCH CAREER DEVELOPMENT AWARD

本提案旨在为主要研究者提供必要的知识和经验 他在肾结石和骨领域的独立临床研究人员的发展， 钙代谢本申请中的研究计划提出探索代谢后果 低碳水化合物高蛋白（LCHP）饮食被广泛用于减肥。饮食 限制碳水化合物的摄入，这导致蛋白质消耗的必然增加。 长期以来，膳食蛋白质的过量摄入被认为会显著增加尿中 钙，增加肾结石形成的风险，并可能导致骨质流失。的目标 研究计划是阐明与钙排泄增加相关的机制。 LCHP饮食我们假设LCHP饮食通过酸负荷、高尿钙、高钙血症和高钙血症诱导高钙尿症。 前列腺素E2（PGE2），或两者。第一个具体目标是检验观察到的高钙尿症 是由饮食中的酸性物质引起的我们将探索柠檬酸钾，一种碱 钾盐，部分或完全逆转LCHP饮食诱导的高钙尿症， 中和所赋予的酸负荷。第二个具体目标是检验高钙尿症 通过增加前列腺素E2（PGE2）的尿排泄的机制发生。我们将测试 吲哚美辛通过改变PGE2逆转LCHP饮食诱导的高钙尿症的能力 生产更好地理解膳食蛋白诱导的高钙尿症的机制将是 在探索流行的LCHP饮食对骨骼的安全性和潜在有害影响方面有价值 还有肾脏除了研究计划外，申请人还建议通过以下方式进一步发展其研究事业： 与从事动物相同领域研究的基础研究人员合作，参加 进行临床研究，并学习骨活检评估技术。

This proposal is designed to provide the principal investigator with the knowledge and experience necessary for his development as an independent clinical researcher in the fields of nephrolithiasis and bone and calcium metabolism. The research plan in this application proposes to explore the metabolic consequences of the popular low-carbohydrate high-protein (LCHP) diet that is widely used for weight reduction. The diet imposes a limitation on carbohydrate intake, which leads to an obligatory increase in protein consumption. Excessive intake of dietary proteins has long been known to significantly raise the urinary excretion of calcium, increasing the risk for kidney stone formation and possibly causing bone loss. The objectives of the research plan are to shed light on the mechanism(s) underlying the increased calcium excretion associated with the LCHP diet. We hypothesize that LCHP diets induce hypercalciuria by acid load, high urinary prostaglandin E2 (PGE2), or both. The first specific aim tests the hypothesis that the observed hypercalciuria is caused by an acid load conferred by the diet. We will explore the ability of potassium citrate, an alkali potassium salt, to either partially or completely reverse the hypercalciuria induced by the LCHP diet by neutralizing the conferred acid load. The second specific aim will test the hypothesis that the hypercalciuria occurs through a mechanism that increases the urinary excretion of prostaglandin E2 (PGE2). We will test the ability of indomethacin to reverse the hypercalciuria induced by the LCHP diet, by altering PGE2 production. A better understanding of the mechanism(s) of dietary protein-induced hypercalciuria will be valuable in exploring the safety and the potential deleterious effects of the popular LCHP diet on the skeleton and the kidney. In addition to the research plan, the applicant proposes to further his research career by collaborating with basic researchers working on the same area in animals, attending didactic courses in clinical research conduct, and learning the techniques of bone biopsy evaluation.