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

• 批准号: 9291584
• 负责人: Marshall Stoller
• 金额: $ 5.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/9291584
• 关键词: Affect; Algorithms; Basic Science; Behavior; Benign; Binding; Biological Markers; Calcium; Calcium Oxalate; 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; metabolome; 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

 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（由申请人提供）：肾结石疾病影响近10%的美国人口，每年为美国医疗保健系统增加50亿美元的财政负担。泌尿系结石的取出已经取得了很大的进步，但在了解或预防结石发病机制方面进展甚微。虽然我们将患者的结石和尿液送去进行化学分析，但结果通常对临床决策影响不大。技术 用于结石分析的方法没有进步，并且仍然是基本的、不可靠的和不可复制的。此外，传统的24小时尿检不能正确预测未来的结石事件，因此在预防结石复发方面的效用有限。最常见的肾结石（约85%）是钙基结石，通常由草酸钙和/或磷酸钙组成。监测尿钙可能是有用的，但不能提供完整的风险评估，并且为了改变全身钙稳态而改变钙摄入量对结石形成没有显著影响。需要新的肾结石疾病生物标志物来改善肾结石疾病的临床管理。我们的良性泌尿科跨学科研究发展中心最近使用果蝇结石形成模型表明，钙以外的金属，包括锌和锶，在肾结石中起着令人惊讶的重要作用。例如，简单地增加膳食锌强烈促进结石形成，而螯合锌或抑制锌转运蛋白则显著减少结石的数量。我们为该中心重新提供资金的提议旨在将这些发现转化为人类肾结石疾病，重点是确认重金属在人类患者队列中结石形成的重要性，并证明尿液和结石样本的综合金属组学和靶向代谢组学分析对预测症状性结石发作的价值。我们将在加州大学弗朗西斯科分校的泌尿系结石诊所随访一组同质性高尿酸尿和/或低柠檬酸尿的钙基结石形成者。将在我们的分析核心设施收集结石和尿液样本并进行广泛的金属组学和代谢组学小组分析。来自人体结石和尿液的金属组学和代谢组学研究结果的综合结果将使我们能够模拟新的诊断和治疗算法，以增强或取代目前实践中已有35年历史的检测方法。我们的目标是确定 金属和代谢物生物标志物的最佳组成，以揭示泌尿系结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，并将为在复发性肾结石患者中开展大型干预研究提供必要的科学基础

项目成果

Clinical Outcomes for Cystinuria Patients with Unilateral Versus Bilateral Cystine Stone Disease.

患有单侧与双侧胱氨酸结石病的胱氨酸尿症患者的临床结果。

• DOI: 10.1089/end.2017.0335
• 发表时间: 2018
• 期刊: Journal of endourology
• 影响因子: 2.7
• 作者: Usawachintachit,Manint;Sherer,Benjamin;Hudnall,Matthew;Tzou,DavidT;Taguchi,Kazumi;Hsi,RyanS;Stoller,Marshall;Chi,Thomas
• 通讯作者: Chi,Thomas

Significant differences in struvite and cystine stone frequency seen among Chinese nephrolithiasis patients living in North America compared to those living in China.

居住在北美的中国肾结石患者与居住在中国的患者相比，鸟粪石和胱氨酸结石的发生率存在显着差异。

• DOI: 10.21037/tau.2016.04.07
• 发表时间: 2016
• 期刊: Translational andrology and urology
• 影响因子: 2
• 作者: Chi,Thomas;Usawachintachit,Manint;Filippou,Pauline;Bayne,David;Hu,Weiguo;Chang,Helena;Xia,Lei;Chen,Qi;Xue,Wei;He,Hui;Long,Qingzhi;Arsovska,Olga;Taylor,Eric;Paterson,Ryan;Sur,RogerL;Chew,Ben;Stoller,MarshallL;Li,Jianxin
• 通讯作者: Li,Jianxin

Optimizing RNA Extraction of Renal Papilla Biopsy Tissue in Kidney Stone Formers: A New Methodology for Genomic Study.

优化肾结石形成者肾乳头活检组织的 RNA 提取：基因组研究的新方法。

• DOI: 10.1089/end.2017.0320
• 发表时间: 2017
• 期刊: J Endourol
• 影响因子: 2.7
• 作者: Taguchi K;Usawachintachit M;Hamamoto S;Unno R;Tzou DT;Sherer BA;Wang Y;Okada A;Stoller ML;Yasui T;Chi T.
• 通讯作者: Chi T.