MENTORED PATIENT-ORIENTED RESEARCH CAREER DEVELOPMENT AWARD

本建议旨在为首席调查员提供必要的知识和经验。 作为一名独立的临床研究员，他在肾结石和骨科领域的发展 钙代谢。该应用程序中的研究计划建议探索代谢后果 广泛用于减肥的低碳水化合物高蛋白(LCHP)饮食中的一种。节食 对碳水化合物的摄入量施加限制，这会导致蛋白质摄入量的强制性增加。 人们早就知道，摄入过量的膳食蛋白质会显著增加尿液中的 钙，增加肾结石形成的风险，并可能导致骨质流失。该计划的目标 研究计划是阐明钙排泄增加背后的机制(S) 用低碳水化合物的饮食。我们假设低密度脂蛋白饮食通过酸负荷、高尿 前列腺素E2(PGE2)，或两者兼而有之。第一个明确的目标是检验这样一个假设，即观察到的高钙尿症 是由饮食产生的酸性负荷引起的。我们将探索柠檬酸钾的能力，一种碱 钾盐可部分或完全逆转LC HP饮食所致的高钙尿症 中和所赋予的酸负荷。第二个具体目标将检验高钙尿症的假设 发生的机制是增加尿中前列腺素E2(PGE2)的排泄量。我们将测试 吲哚美辛通过改变前列腺素E_2逆转低钙饮食所致高钙尿的作用 制作。要更好地理解膳食蛋白质引起的高钙尿症的机制(S)将是 在探索流行的低碳水化合物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，申请者还建议通过以下方式进一步发展他的研究事业 与动物同一领域的基础研究人员合作，参加 进行临床研究，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.