Obesity and Endogenous Oxalate Synthesis

肥胖与内源性草酸盐合成

• 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
• 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

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.

项目总结/摘要 这一建议将使我的研究生涯的指导下，经验和监护的进步， 成功和有效的导师。此外，我的研究知识将通过培训， 研究、动物实验和复杂的代谢分析技能。这个提议会给我必要的工具 成为一名独立调查员最后，建议的研究为我提供了继续研究的机会 我目前的研究努力，特别是在肾结石疾病，内源性草酸合成， 以及肥胖的作用。 在过去的几十年里，美国肾结石疾病的患病率呈线性增长， 影响了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，饮食和环境。多种医学合并症与肾结石有关 包括肥胖症在内的疾病。最常见的结石成分之一是草酸盐， 新陈代谢的产物。尿草酸盐的少量增加可增加草酸钙晶体的形成， 因此结石病。多项流行病学研究表明，肥胖与 和尿草酸排泄。然而，对于这种尿量增加的根本原因知之甚少。 草酸盐。 尿草酸盐水平受饮食和内源性成分的影响，每种成分都有贡献 平等地内源性草酸盐的合成以前被认为主要发生在肝脏，其主要的代谢途径是肝细胞。 来源是乙醛酸。草酸盐产生的生化途径知之甚少， 广泛的研究。中心假设是肥胖患者尿草酸盐的增加是由于 增加了内源性生产。此外，提出肥胖影响代谢过程 在肝脏内，导致草酸盐合成增加。这些假设将通过两个具体的 目的：1）评估在瘦和饮食诱导的肥胖动物模型中的草酸盐合成，2）为了证明 肥胖的人在控制饮食时增加了内源性草酸盐的合成。我会把我们的实验室 在人类和小鼠的控制饮食研究方面的专业知识，并利用复杂的分析技术， 包括基于质谱的分析。 这项研究可能为肥胖和脂肪分布在内源性肥胖中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病。这将有助于我转变为一个 独立和富有成效的NIH资助的调查员。