Obesity and Endogenous Oxalate Synthesis

项目摘要/摘要 这项建议将使我的研究事业在我的指导、经验和指导下取得进展 成功而有效的导师。此外，我的研究知识将通过人类的培训而得到加强 研究、动物工作和复杂的代谢分析技能。这项提议将给我必要的工具 成为一名独立调查员。最后，拟议的研究为我提供了继续的机会 我目前的研究重点是肾结石疾病，内源性草酸合成， 以及肥胖的作用。 在过去的几十年里，肾结石疾病在美国的患病率呈线性上升 折磨着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。多种内科合并症与肾结石有关 包括肥胖在内的疾病。最常见的石材成分之一是草酸盐，一种末端 新陈代谢产物。尿草酸少量增加可增加草酸钙晶体的形成和 因此，结石病。多项流行病学研究表明，肥胖与 以及尿液草酸排泄量。然而，人们对尿液增加的潜在原因知之甚少。 草酸盐。 尿草酸水平既受饮食因素的影响，也受内源性成分的影响，人们认为这两种因素对尿草酸水平都有影响。 同样如此。内源性草酸的合成以前被认为主要发生在肝脏和主要的 来源是乙醛。参与草酸生产的生化途径知之甚少，尽管 广泛的研究。中心假设是肥胖症患者尿草酸的增加是源于 来自内源产量的增加。此外，还提出肥胖影响新陈代谢过程。 在肝脏内，导致草酸合成增加。这些假说将通过追求两个具体的 目的：1)评估瘦肉和饮食诱导的肥胖动物模型中草酸的合成，2)证明 肥胖的人在受控饮食中增加了内源性草酸的合成。我会把我们的实验室 在人类和小鼠的受控饮食研究方面的专业知识，并利用复杂的分析技术， 包括基于质谱学的分析。 这项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。 草酸钙的产生从而导致肾结石草酸钙的产生。这将有助于我过渡到 美国国立卫生研究院资助的独立且高效的研究人员。

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.