Obesity and Endogenous Oxalate Synthesis

肥胖与内源性草酸盐合成

基本信息

批准号：
10457943
负责人：
Kyle D Wood
金额：
$ 16.68万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10457943
关键词：
Adult Affect Alanine-glyoxylate aminotransferase Animal Experimentation Animal Model Animals Basic Science Biochemical Biochemical Pathway Biological Assay Body fat Body mass index Calcium Calcium Oxalate Complex Crystal Formation Data Diet Disease Dual-Energy X-Ray Absorptiometry Environment Enzymes Epidemiology Etiology Excretory function Failure Fatty acid glycerol esters Funding Future Genetic Glutathione Glycolates Goals Hepatic High Fat Diet High Prevalence Human Kidney Calculi Knowledge Laboratories Lactate Dehydrogenase Link Liver Magnetic Resonance Imaging Mass Spectrum Analysis Measures Medical Mentors Metabolic Metabolic Pathway Metabolism Mus Obese Mice Obesity Obesity Epidemic Overweight Oxalates Oxidases Pathway interactions Plasma Population Prevalence Production Prospective cohort Research Research Personnel Risk Role Site Source Southeastern United States Technology Testing Thinness Tissues Training Translational Research United States United States National Institutes of Health Waist-Hip Ratio Weight Weight Gain Work aldehyde dehydrogenases base career cohort comorbidity diet-induced obesity dietary epidemiology study experience experimental study feeding glyoxylate glyoxylate reductase high body mass index human subject insight lifestyle factors mouse model obese person skills stable isotope tool urinary waist circumference

项目摘要

Project Summary/Abstract This proposal will enable advancement of my research career under the guidance, experience, and tutelage of successful and effective mentors. In addition, my research knowledge will be augmented by training in human studies, animal work and the complex metabolic analytical skills. This proposal will give me the tools necessary to become an independent investigator. Finally, the proposed study provides me the opportunity to continue my current research endeavors, specifically looking at kidney stone disease, endogenous oxalate synthesis, and the role of obesity. The prevalence of kidney stone disease linearly increased in the U.S. over the last several decades, now afflicting 10-15% of the population. The etiology of kidney stone disease is multifactorial involving lifestyle factors, genetics, diet, and environment. Multiple medical comorbidities have been linked to kidney stone disease including obesity. One component of the most common type of stone composition is oxalate, an end product of metabolism. Small increases in urinary oxalate can increase calcium oxalate crystal formation and thus stone disease. Multiple epidemiological studies have demonstrated a positive correlation between obesity and urinary oxalate excretion. Yet, little is known about the underlying reason for this increase in urinary oxalate. Urinary oxalate levels are affected by both a dietary and endogenous component and each is felt to contribute equally. Endogenous oxalate synthesis has been previously thought to occur primarily in the liver and its major source is glyoxylate. The biochemical pathways involved in oxalate production are poorly understood despite extensive research. The central hypothesis is that the increase in urinary oxalate seen in obesity is derived from increased endogenous production. Further, it is proposed that obesity influences the metabolic processes within the liver, resulting in increased oxalate synthesis. The hypotheses will be tested by pursuing two specific aims: 1) Evaluating oxalate synthesis in a lean and a diet-induced obese animal model, 2) To demonstrate that obese humans have increased endogenous oxalate synthesis on controlled diets. I will apply our laboratories expertise in controlled dietary studies in both humans and mice, and utilize complex analytical technologies, including mass spectrometry based assays. The proposed study may provide new insights regarding the role of obesity and fat distribution on endogenous oxalate production and thus calcium oxalate kidney stone disease. It will facilitate my transition into an independent and productive NIH funded investigator.

项目概要/摘要该提案将使我的研究事业在以下人士的指导、经验和指导下取得进步：成功且有效的导师。此外，我的研究知识将通过人类培训得到增强研究、动物工作和复杂的代谢分析技能。该提案将为我提供必要的工具成为一名独立调查员。最后，拟议的研究为我提供了继续学习的机会我目前的研究工作，特别是肾结石疾病、内源性草酸合成、以及肥胖的作用。过去几十年来，美国肾结石患病率呈线性增加，现在影响10-15%的人口。肾结石的病因是多因素的，涉及生活方式因素、遗传、饮食、环境。多种合并症与肾结石有关包括肥胖在内的疾病。最常见的石材成分中的一种成分是草酸盐，一种末端新陈代谢的产物。尿草酸的少量增加会增加草酸钙晶体的形成，从而形成结石病。多项流行病学研究表明肥胖与肥胖之间呈正相关和尿草酸排泄。然而，对于尿量增加的根本原因知之甚少。草酸盐。尿草酸盐水平受到饮食和内源性成分的影响，并且每种成分都被认为有所贡献平等地。内源性草酸盐合成以前被认为主要发生在肝脏及其主要器官中。来源是乙醛酸盐。尽管人们对草酸产生所涉及的生化途径知之甚少广泛的研究。中心假设是肥胖者尿草酸盐的增加源自来自内生产量的增加。此外，有人认为肥胖会影响代谢过程在肝脏内，导致草酸合成增加。这些假设将通过追求两个具体的目标：1) 评估瘦动物模型和饮食诱导的肥胖动物模型中的草酸盐合成，2) 证明肥胖的人在控制饮食的情况下会增加内源性草酸盐的合成。我将应用我们的实验室人类和小鼠受控饮食研究的专业知识，并利用复杂的分析技术，包括基于质谱的分析。拟议的研究可能为肥胖和脂肪分布对内源性的作用提供新的见解。草酸盐的产生，从而导致草酸钙肾结石疾病。这将有助于我过渡到独立且富有成效的 NIH 资助的研究人员。