MENTORED PATIENT-ORIENTED RESEARCH CAREER DEVELOPMENT AWARD

描述（由申请人提供）： 本提案旨在为主要研究者提供必要的知识和经验，使其成为肾结石和骨钙代谢领域的独立临床研究者。本申请中的研究计划旨在探索广泛用于减肥的流行低碳水化合物高蛋白（LCHP）饮食的代谢后果。饮食对碳水化合物的摄入施加了限制，这导致蛋白质消耗的强制性增加。长期以来，人们都知道过量摄入膳食蛋白质会显著增加钙的尿排泄，增加肾结石形成的风险，并可能导致骨质流失。研究计划的目的是阐明与LCHP饮食相关的钙排泄增加的机制。我们假设LCHP饮食通过酸负荷、高尿前列腺素E2（PGE2）或两者引起高钙尿症。第一个具体目的是检验观察到的高钙尿症是由饮食所赋予的酸负荷引起的假设。我们将探索柠檬酸钾（一种碱性钾盐）通过中和所赋予的酸负荷来部分或完全逆转LCHP饮食诱导的高钙尿症的能力。第二个具体目标是检验高钙尿症是通过增加前列腺素E2（PGE2）尿排泄的机制发生的假设。我们将测试吲哚美辛通过改变PGE2的产生来逆转LCHP饮食诱导的高钙尿症的能力。更好地理解膳食蛋白诱导的高钙尿症的机制将有助于探索流行的LCHP饮食对骨骼和肾脏的安全性和潜在有害影响。除了研究计划外，申请人还提议通过与动物相同领域的基础研究人员合作、参加临床研究实施的教学课程以及学习骨活检评估技术来进一步发展他的研究事业。

DESCRIPTION (provided by applicant): 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.