Optimizing Kidney Stone Management Using Metallomics and Metabolomics

利用金属组学和代谢组学优化肾结石管理

基本信息

批准号：
9040711
负责人：
Marshall Stoller
金额：
$ 31.7万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9040711
关键词：
Affect Algorithms Basic Science Behavior Benign Binding Biological Markers Calcium Calcium Oxalate Calculi California Chemicals Chemistry Clinic Clinical Clinical Management Clinical assessments Collection Communities Core Facility Cystine Development Diagnostic Dietary Zinc Discipline Disease Disease Progression Drosophila melanogaster Event Fostering Foundations Functional disorder Funding Future Generations Goals Health Healthcare Systems Heavy Metals High School Student Homeostasis Hour Human Incidence Institutes Interdisciplinary Study International Intervention Intervention Studies Invertebrates Kidney Calculi Lead Medical Metals Methods Modeling Monitor Morbidity - disease rate Mus Nephrolithiasis Pathogenesis Patients Pattern Play Population Positioning Attribute Prevention Process Publications Recurrence Research Research Personnel Research Project Grants Resources Risk Risk Assessment Role Rubidium Sampling San Francisco Scientist Series Site Source Strontium Sulfur Techniques Testing Therapeutic Trace Elements Translating United States Universities Update Uric Acid Urinary Calculi Urine Urology Visit Work Zinc base biomineralization bone calcium intake calcium phosphate clinical decision-making clinical practice cohort fly improved interdisciplinary approach lectures meetings metabolomics mineralization mortality mouse model novel novel diagnostics novel therapeutics outreach prevent professor research study scaffold small molecule symposium tool treatment strategy urinary web site zinc-binding protein

项目摘要

DESCRIPTION (provided by applicant): Kidney stone disease affects nearly 10% of the US population and annually adds $5 billion in financial burden to the US healthcare system. Great strides have been made in the extraction of urinary stones, yet little progress has been made in understanding or preventing stone pathogenesis. While we send patient stones and urine for chemical analysis, the results typically have little impact on clinical decision-making. Techniques for stone analysis have not advanced and remain rudimentary, unreliable, and unreproducible. Moreover, traditional 24-hour urine testing does not correctly predict future stone events and thus has limited utility in preventing stone recurrence. The most common (~85%) of kidney stones are calcium-based stones, usually composed of calcium oxalate and/or calcium phosphate. Monitoring urinary calcium can be useful, but does not provide a complete assessment of risk, and modifying calcium intake in order to change whole body calcium homeostasis does not had a significant impact on stone formation. New biomarkers of kidney stone disease are needed to improve the clinical management of kidney stone disease. Our Developmental Center for Interdisciplinary Research in Benign Urology has recently shown that metals other than calcium, including zinc and strontium, play a surprisingly important role in nephrolithiasis, using a Drosophila melanogaster model of stone formation. For example, simply increasing dietary zinc strongly promotes stone formation while chelating zinc or inhibiting zinc transporters dramatically reduces the number of stones. Our proposal to renew funding for the Center aims to translate these findings to human kidney stone disease by focusing on confirming the importance of heavy metals in stone formation in a human cohort of patients and demonstrating the value of comprehensive metallomic and targeted metabolomics analysis of urine and stone samples for predicting symptomatic stone episodes. We will follow a homogenous group of calcium-based stone formers with hyperuricosuria and/or hypocitraturia in our urinary stone clinic at the University of California San Francisco. Stone and urine samples will be collected and analyzed for a broad metallomic and metabolomics panel at our Analytic Core Facility. The combined results of both the metallomic and metabolomic findings from human stones and urine will then allow us to model new diagnostic and therapeutic algorithms to augment or replace the 35-year-old testing method currently in practice. Our goal is to identify the optimal composition of metal and metabolite biomarkers to reveal new aspects of urinary stone pathophysiology and to develop practical diagnostic and therapeutic tools. These methods will create a much-needed modern resource for broad urology community and will provide the necessary scientific foundation to launch a large intervention study in patients with recurrent kidney stone disease

描述（由适用提供）：肾脏疾病影响美国人口的近10％，每年在美国医疗保健系统中增加50亿美元的财务燃烧。在提取尿石方面取得了长足的进步，但是在理解或预防石材发病机理方面几乎没有取得进步。当我们发送患者石头和尿液进行化学分析时，结果通常对临床决策几乎没有影响。技术对于石材，分析没有进步，并且保持基本，不可靠且难以捉摸。此外，传统的24小时尿液测试无法正确预测未来的石材事件，因此在预防石材复发方面的效用有限。最常见的（〜85％）肾结石是基于钙的结石，通常由草酸钙和/或磷酸钙组成。监测尿钙可能很有用，但不能完全评估风险，并修改钙摄入以改变全身钙稳态的钙稳态不会对石材的形成产生重大影响。需要新的肾结石疾病生物标志物来改善肾结石的临床管理。我们的良性泌尿科跨学科研究中心最近表明，包括锌和锶在内的钙以外的金属在肾石器症中起着令人惊讶的重要作用，使用果蝇的石材形成模型。例如，简单地增加饮食锌会强烈促进石材的形成，同时螯合锌或抑制锌转运蛋白会大大减少石头的数量。我们为该中心续签资金的建议旨在通过确认重金属在人类人群中重金属形成中重金属的重要性，并证明对尿液和石材样品的综合金属和靶向代谢组分析预测有症状的石头发作的价值。我们将在加利福尼亚大学旧金山分校的尿石诊所中跟随一组具有高尿尿和/或低脂性的基于钙的石材形成器。将在我们的分析核心设施中收集并分析石材和尿液样品，并分析用于广泛的金属组和代谢组合面板。然后，来自人类石头和尿液的金属粒和代谢组发现的综合结果将使我们能够对新的诊断和治疗算法进行建模，以增强或替换当前实践中现有的35年历史的测试方法。我们的目标是确定金属和代谢物生物标志物的最佳组成揭示了尿石病理生理学的新方面并开发实用的诊断和治疗工具。这些方法将为广泛的泌尿外科社区创造急需的现代资源，并将为重复肾脏疾病的患者启动大型干预研究提供必要的科学基础