Dietary Oxalate and Innate Immunity in Kidney Stone Disease

膳食草酸盐与肾结石疾病的先天免疫

• 批准号: 10116373
• 负责人: Tanecia R Mitchell
• 金额: $ 10.82万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-28 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116373
• 关键词: Address; Affect; Animal Model; Blood Circulation; Calcium Oxalate; Cell Line; Cells; Characteristics; Complement; Complex; Consumption; Crystal Formation; Crystallization; Data; Data Display; Deposition; Development; Diet; Disease; Electron Transport; Excretory function; Female; Flow Cytometry; Foundations; Funding; Generations; Genetic; Genus Hippocampus; Goals; Grant; Health Care Costs; Histology; Homeostasis; Immune; Immune response; Immune system; Inflammation; Inflammatory; Inflammatory Response; Intake; Kidney; Kidney Calculi; Knowledge; Lead; Macrophage Activation; Mediating; Mentored Research Scientist Development Award; Metabolism; Minerals; Mitochondria; Molecular Biology; Natural Immunity; Nephrons; Oxalates; Oxidation-Reduction; Oxidative Stress; Pain; Pathogenesis; Patients; Phagocytosis; Population; Proline; Property; Proteins; Quality of life; Rattus; Reactive Oxygen Species; Recurrence; Reporting; Research; Risk; Risk Factors; Role; Signal Pathway; Signal Transduction; Sodium Chloride; Sprague-Dawley Rats; Systemic disease; Technology; Testing; United States; Urine; chemokine; cytokine; dietary; effective intervention; experimental study; human subject; immunological status; kidney cell; lifestyle factors; macrophage; male; monocyte; nanocrystal; nephrogenesis; novel strategies; prevent; recruit; renal epithelium; response; therapeutic target; tool; transcriptome; transcriptome sequencing; urinary

PROJECT SUMMARY: Kidney stone (KS) disease is becoming more prevalent in the United States and is associated with systemic diseases and lifestyle factors such as diet. A major risk factor for stone formation is an elevation in urinary oxalate, which can be derived endogenously or from the diet. Dietary oxalate intake may induce supersaturation of calcium oxalate (CaOx) which may generate crystals of this stone forming salt in urine and perhaps the nephron. CaOx crystals that interact with renal epithelium activate innate immunity by releasing cytokines and chemokines to stimulate monocyte recruitment. We previously reported that patients with CaOx kidney stone (CaOx KS) disease have altered monocyte cellular energetics and increased inflammation. In addition, we have shown oxalate directly disrupts cellular energetics and redox homeostasis in monocytes from healthy subjects. The long-term goal of this research is to understand how oxalate impacts monocyte and macrophage immunometabolism in KS disease. The objective of the current study is to investigate the relationship between urinary crystals, macrophage activation, reactive oxygen species (ROS), and pro- inflammatory signaling pathways following oxalate consumption. The central hypothesis is oxalate disrupts mitochondrial complex I activity in monocytes and stimulates ROS generation, pro-inflammatory macrophage differentiation, and renal crystal deposition in CaOx KS disease. Aim 1 will test the hypothesis that oxalate stimulates reverse electron transport (RET) through mitochondrial complex I in monocytes from healthy subjects. Aim 2 will test the hypothesis that oxalate mediated crystalluria induces ROS and disrupts macrophage immunometabolism in rat kidneys. No studies to date have investigated the connection between dietary oxalate, crystalluria, and immune responses in CaOx KS disease. A novel approach to assess urinary nanocrystals and their influence on monocytes and macrophages will be investigated. The impact of this research will help us understand how monocytes and macrophages respond to crystals, and may identify potential approaches to assess stone risk, reduce stone formation, and stone recurrence. The data generated from this proposal will advance our knowledge about the role of dietary oxalate on immune cells in KS disease and serve as a key foundation for subsequent R01 funding.

项目概要： 肾结石（KS）疾病在美国变得越来越普遍，并与全身性 疾病和生活方式因素，如饮食。结石形成的一个主要危险因素是泌尿系统的升高。 草酸盐，它可以来自内源性或从饮食。膳食草酸盐摄入可能会导致 草酸钙（CaOx）的过饱和，这可能会在尿液中产生这种结石形成盐的晶体， 可能是肾单位。与肾上皮相互作用的CaOx晶体通过释放 细胞因子和趋化因子以刺激单核细胞募集。我们以前报道过CaOx患者 肾结石（CaOx KS）疾病改变了单核细胞能量学并增加了炎症。在 此外，我们已经表明草酸盐直接破坏单核细胞的细胞能量学和氧化还原稳态， 例正常人这项研究的长期目标是了解草酸盐如何影响单核细胞， KS病中的巨噬细胞免疫代谢。本研究的目的是调查 尿结晶、巨噬细胞活化、活性氧（ROS）和促红细胞生成素之间的关系 草酸消耗后的炎症信号通路。核心假设是草酸盐破坏 单核细胞中的线粒体复合物I活性并刺激ROS生成，促炎巨噬细胞 分化和CaOx KS病中的肾晶体沉积。目的1将测试假设，草酸 刺激来自健康人的单核细胞中通过线粒体复合物I的反向电子传递（RET） 科目目的2将验证草酸盐介导的晶状体形成诱导ROS并破坏 巨噬细胞免疫代谢。到目前为止，还没有研究调查 CaOx KS病中的饮食草酸盐、晶体和免疫反应。一种新的方法来评估尿 将研究纳米晶体及其对单核细胞和巨噬细胞的影响。这样做的影响 研究将帮助我们了解单核细胞和巨噬细胞如何对晶体做出反应，并可能识别 评估结石风险、减少结石形成和结石复发的潜在方法。生成的数据 该提案将推进我们对KS疾病中饮食草酸盐对免疫细胞作用的认识 并作为后续R01资金的关键基础。