MENTORED PATIENT-ORIENTED RESEARCH CAREER DEVELOPMENT AWARD

描述(由申请人提供)： 这项建议旨在为首席研究员提供必要的知识和经验，使其成为肾结石、骨和钙代谢领域的独立临床研究员。该应用程序的研究计划建议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量施加了限制，这导致了蛋白质摄入量的强制性增加。人们早就知道，过量摄入膳食蛋白质会显著增加尿钙的排泄，增加肾结石形成的风险，并可能导致骨质流失。该研究计划的目标是阐明与低钙饮食相关的钙排泄增加的机制(S)。我们假设低密度脂蛋白饮食通过酸负荷或高尿前列腺素E_2(PGE_2)，或两者兼而有之而导致高钙尿。第一个具体目的是检验这样一种假设，即观察到的高钙尿症是由饮食中的酸性负荷引起的。我们将探索柠檬酸钾，一种碱性钾盐，通过中和所提供的酸负荷，部分或完全逆转由LCHP饮食引起的高钙尿症的能力。第二个具体目标将检验这一假设，即高钙尿症是通过增加尿前列腺素E2(PGE2)排泄的机制发生的。我们将通过改变PGE2的产生来测试吲哚美辛逆转由LCHP饮食引起的高钙尿的能力。更好地了解饮食蛋白质引起高钙尿的机制(S)将有助于探索流行的低钙饮食的安全性和对骨骼和肾脏的潜在有害影响。除了研究计划外，申请者还建议通过与从事动物同一领域工作的基础研究人员合作，参加临床研究指导课程，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.