Origin of Excess Acid in Uric Acid Urolithiasis

尿酸尿石症中酸过多的根源

基本信息

批准号：
10442425
负责人：
JEFFREY D BROWNING
金额：
$ 44.97万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-05 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10442425
关键词：
16S ribosomal RNA sequencing Acids Address Aging Alkalinization American Ammonia Animals Antibiotics Bacteria Bacterial Model Biochemical Biochemistry Bioinformatics Biometry Blood Buffers Chemistry Clinical Communities Data Defect Diabetes Mellitus Diet Etiology Excretory function Fatty Acids Fatty Liver Fatty acid glycerol esters Feces Female Fibrinogen Frequencies Functional disorder Generations Germ-Free Healthcare Hepatic Hepatocyte High Fat Diet Human Impairment Infiltration Integration Host Factors Intestines Investigation Kidney Kidney Calculi Lead Leptin Liver Matched Group Measurement Measures Metabolic Metabolic syndrome Modeling Mus NMR Spectroscopy Nephrolithiasis Non obese Obesity Oral Pathogenicity Pathology Patients Phenotype Pioglitazone Plasma Precipitation Prevalence Production Propionates Rattus Research Personnel Resolution Reverse Transcriptase Polymerase Chain Reaction Risk Serum Shotguns Source Testing Thinness Titrations Transplantation Urate Uric Acid Urine Virulence Factors analysis pipeline care burden cost diabetic disease phenotype experimental study fecal microbiome gut bacteria gut microbiota host microbiota human subject in vivo insight liver metabolism male metabolomics metagenomic sequencing microbial microbial genome microbiome microbiome analysis microbiota microbiota transplantation microorganism novel novel therapeutics obese patients organic acid urinary urolithiasis

16S ribosomal RNA sequencing Acids Address Aging Alkalinization American Ammonia Animals Antibiotics Bacteria Bacterial Model Biochemical Biochemistry Bioinformatics Biometry Blood Buffers Chemistry Clinical Communities Data Defect Diabetes Mellitus Diet Etiology Excretory function Fatty Acids Fatty Liver Fatty acid glycerol esters Feces Female Fibrinogen Frequencies Functional disorder Generations Germ-Free Healthcare Hepatic Hepatocyte High Fat Diet Human Impairment Infiltration Integration Host Factors Intestines Investigation Kidney Kidney Calculi Lead Leptin Liver Matched Group Measurement Measures Metabolic Metabolic syndrome Modeling Mus NMR Spectroscopy Nephrolithiasis Non obese Obesity Oral Pathogenicity Pathology Patients Phenotype Pioglitazone Plasma Precipitation Prevalence Production Propionates Rattus Research Personnel Resolution Reverse Transcriptase Polymerase Chain Reaction Risk Serum Shotguns Source Testing Thinness Titrations Transplantation Urate Uric Acid Urine Virulence Factors analysis pipeline care burden cost diabetic disease phenotype experimental study fecal microbiome gut bacteria gut microbiota host microbiota human subject in vivo insight liver metabolism male metabolomics metagenomic sequencing microbial microbial genome microbiome microbiome analysis microbiota microbiota transplantation microorganism novel novel therapeutics obese patients organic acid urinary urolithiasis

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项目摘要

Project Summary/Abstract Uric acid urolithiasis composes up to about 10% of kidney stones and is increasing in prevalence contemporaneously with the escalating prevalence of obesity, metabolic syndrome, and diabetes. Uric acid urolithiasis is the renal manifestation of the multi-systemic disturbances in obesity, metabolic syndrome and diabetes. The primary pathophysiologic feature of uric acid urolithiasis is excessive aciduria. We propose a multi-organ pathogenic model of uric acid urolithiasis traceable to intestinal organic acid generation by the gut microbiota (totality of the microbial fauna) that escapes complete hepatic metabolism due to subtle defects in the liver from steatosis, which then imposes an increased acid load on the kidneys. Defective ammoniagenesis in the kidney from renal steatosis mandates excretion of the excess acid carried by alternative buffers including urate which ultimately leads to uric acid precipitation and stones. In this model, the first step in uric acid urolithiasis starts in the gut and liver. This proposal will use a combination of animal and human studies to test the hypothesis of the gut and liver as pathogenic origin of uric acid kidney stones. We propose three Aims to address: 1. Microbiota-phenotype association. Microbiome (microbial genome) from uric acid stone formers, obese, and lean non-stone-formers will be correlated with plasma and urinary parameters. 2. Microbiota-phenotype causation. Causality will be tested by transplantation of the microbiota from the three groups of humans from Aim 1 into germ-free mice and we will examine whether the appropriate phenotype is conferred. 3. Microbiota-host interaction. We will test the hypothesis that increased acid production from the microbiota is necessary but not sufficient to confer the disease phenotype. Additional host factors need to be invoked; specifically impaired hepatic metabolism of the lumen-derived organic acids from fatty infiltration of hepatocytes. We will use both animals and humans for all Aims drawing expertise from a diverse synergistic team of human researchers, animal pathophysiologists, microbiota biologists, and bioinformaticians to test our model. These experiments are the first to explore the very origin of the acid load in uric acid urolithiasis, and take the study and treatment of uric acid urolithiasis from empirical management by urinary alkalinization to a genuine and thorough elucidation of its pathophysiology, and subsequent definitive therapy. The studies also open up novel lines of investigation of the pathobiology of microbiota-host interaction in the metabolic syndrome.

项目摘要/摘要尿酸尿石症占肾结石的约10％，并且患病率正在增加同时，肥胖，代谢综合征和糖尿病的流行率不断升高。尿酸尿石症是肥胖中多系统障碍的肾脏表现，代谢综合征和糖尿病。尿酸尿液石病的主要病理生理特征是过多的酸尿。我们提出了尿酸尿石病的多器官致病模型可追溯到肠道微生物群（微生物动物群的总体）生成肠道有机酸由于脂肪变性的肝脏细微缺陷，这逃脱了完全的肝代谢，然后在肾脏上施加增加的酸负荷。肾脏中有缺陷来自肾脏脂肪变性，将替代缓冲液携带的过量酸排泄，包括尿酸盐最终导致尿酸沉淀和石头。在此模型中，第一步尿酸尿石症开始于肠道和肝脏。该提议将结合动物和人类研究测试肠道和肝脏作为尿酸肾脏的致病起源的假设石头。我们提出三个目的解决：1。微生物型 - 表型关联。微生物组（微生物基因组）来自尿酸石材，肥胖和瘦的非石材形成者的（微生物基因组）与血浆和尿参数相关。 2。微生物群 - 表型因果关系。因果关系通过从AIM 1中从三组人中移植微生物群来测试无菌小鼠，我们将检查是否赋予适当的表型。 3。微生物群 - 主持人相互作用。我们将检验以下假设，即增加了来自微生物群是必要的，但不足以赋予疾病表型。其他宿主因素需要调用；特别损害了腔源性有机酸的肝代谢从肝细胞的脂肪浸润。我们将使用动物和人类来绘画来自人类研究人员，动物病理生理学家的各种协同团队的专业知识，微生物群生物学家和生物信息学家测试我们的模型。这些实验是第一个探索尿酸尿石症中酸负荷的起源，并进行研究和治疗通过尿碱化到真正的和真实的和彻底阐明其病理生理学以及随后的确定治疗。研究也是如此打开对微生物群 - 宿主相互作用病理学的新型研究线代谢综合征。