Novel Pathways for Kidney Stone Formation

肾结石形成的新途径

• 批准号: 10356034
• 负责人: ERIC N TAYLOR
• 金额: $ 69.63万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-09 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10356034
• 关键词: Affect; Alkalies; Androgen Receptor; Androgens; Archives; Bacteria; Bifidobacterium; Body Size; Calcium; Calcium Oxalate; Case-Control Studies; Chronic Disease; Citrates; Clinic; Cohort Studies; Collection; Consumption; Cost of Illness; Cross-Sectional Studies; Crystallization; Data; Development; Diet; Disease; Ecology; Epidemiology; Estrogens; Estrone; Estrone-Sulfate; Evaluation; Excretory function; Follow-Up Studies; Foundations; Gas Chromatography; Goals; Gonadal Steroid Hormones; Health Professional; Hepatic; Hour; Individual; Intake; Intestines; Investigation; Kidney Calculi; Lactobacillus; Lead; Life Style; Liquid Chromatography; Mass Spectrum Analysis; Measures; Mediating; Metabolic Pathway; Metagenomics; Microbial Taxonomy; Nephrolithiasis; Nested Case-Control Study; Nurses' Health Study; Organism; Oxalates; Oxalobacter; Oxalobacter formigenes; Pain; Pathogenesis; Pathway interactions; Patients; Persons; Plasma; Play; Population Study; Potassium; Prevalence; Prevention; Prevention strategy; Principal Component Analysis; Production; Recurrence; Reporting; Research Design; Resources; Risk; Risk Factors; Role; Sampling; Sex Differences; Statistical Methods; Steroids; Testosterone; Urinary Calculi; Urine; Woman; absorption; androgenic; base; biobank; case control; cost; dehydroepiandrosterone; dietary; disorder risk; equol; follow-up; fruits and vegetables; gut bacteria; gut microbiome; gut microbiota; inhibitor; insight; men; metabolomics; microbial; network models; novel; promoter; prospective; secondary analysis; stool sample; treatment strategy; urinary

PROJECT SUMMARY/ABSTRACT Kidney stones are common, costly, and painful, and may lead to the development of many chronic diseases. Despite advances delineating mechanisms of kidney stone formation and identifying risk factors, little has changed in the evaluation and management of the patient in the kidney stone prevention clinic during the last 20 years. Furthermore, kidney stone recurrence rates remain stubbornly high. The goal of our proposed studies is to provide new insights into the pathogenesis of stone formation that eventually will lead to the development of new treatment and/or prevention strategies. We propose to leverage the resources of the Nurses' Health Study II (NHS II) and the Health Professionals Follow-up Study (HPFS), ongoing cohort studies with decades of follow-up and rich dietary, lifestyle, and biorepository data, to conduct the first large-scale population based study (N = 800) of the intestinal microbiome and kidney stones (Aim 1), and to perform the first prospective, plasma and urine metabolomics- based study (N = 1200) of kidney stone formation (Aim 2). Intestinal microbiota may play a role in kidney stone formation by altering the absorption and subsequent urinary excretion of a wide variety of lithogenic factors. A small study reported a distinct gut microbiome in stone formers compared with controls. However, it is unknown whether differences in intestinal flora contribute to stone formation or instead represent microbial `markers' of established kidney stone risk factors such as diet and body size. In our case-control study in Aim 1, we will use stool samples from NHS II to define the intestinal microbial taxonomic and metagenomic functional ecologies in individuals with nephrolithiasis, independent of diet and body size. We also will examine associations between the intestinal microbiome and 24-hour urine composition. In prospective, nested case-control studies within NHS II and HPFS (Aim 2), we will use state-of-the-art liquid or gas chromatography followed by mass spectrometry platforms to identify > 1300 metabolites from plasma and urine. In targeted metabolomic analyses, we will identify independent associations between circulating sex hormones, microbial derived metabolites, and kidney stone risk. In untargeted metabolomic analyses, we seek to discover novel metabolite signatures associated with kidney stone formation. We will use principal component analysis and other advanced statistical methods to build distinct metabolite signatures that use all the measured plasma and urine metabolite data to distinguish kidney stone cases from controls.

项目摘要/摘要 肾结石很常见，昂贵且痛苦，可能导致许多慢性疾病的发展。 尽管进步了描述肾结石形成和识别危险因素的机制，但几乎没有 在上次 20年。此外，肾结石复发率仍然很高。我们提议的目标 研究是为了对石材形成的发病机理提供新的见解，最终将导致 制定新待遇和/或预防策略。 我们建议利用护士健康研究II（NHS II）和卫生专业人员的资源 随访研究（HPF），正在进行的队列研究，具有数十年的随访和丰富的饮食，生活方式和 生物验证数据，用于进行肠道的首次大规模基于人群的研究（n = 800） 微生物组和肾结石（AIM 1），并执行第一个前瞻性，血浆和尿液代谢组学 - 基于肾结石形成的研究（n = 1200）（AIM 2）。 肠道菌群可能通过改变吸收和随后的方式在肾结石形成中起作用 多种岩性因子的尿液排泄。一项小型研究报告了一个独特的肠道微生物组 与对照组相比，石材形成器。但是，尚不清楚肠道菌群的差异是否贡献 形成石头或代表已建立肾脏石危险因素（例如饮食）的微生物“标记” 和身体大小。在AIM 1中的病例对照研究中，我们将使用NHS II的粪便样品来定义肠道 肾石石症个体中的微生物分类学和宏基因组功能生态学，独立于 饮食和体型。我们还将检查肠道微生物组和24小时尿液之间的关联 作品。 在NHS II和HPF中的潜在的，嵌套的病例对照研究（AIM 2）中，我们将使用最先进的液体 或气相色谱法，然后是质谱平台，以识别血浆中的1300代谢 和尿液。在有针对性的代谢组分析中，我们将确定循环性别之间的独立关联 激素，微生物衍生的代谢产物和肾结石风险。在不靶向的代谢组分析中，我们寻求 发现与肾结石形成相关的新型代谢物特征。我们将使用校长 组件分析和其他高级统计方法，用于构建所有使用全部的代谢物特征 测量的血浆和尿液代谢产物数据将肾结石病例与对照区分开。