Hereditary Causes of Nephrolithaisis and Kidney Failure

肾结石和肾衰竭的遗传原因

基本信息

批准号：
8328112
负责人：
Dawn Schmautz Milliner
金额：
$ 122.44万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-08 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8328112
关键词：
Abdominal colic Accounting Address Adenine Adult Affect Age Alanine-glyoxylate aminotransferase Area Automobile Driving Biological Markers Calcium Oxalate Calculi Caring Case Study Cells Cellular biology Childhood Chloride Channels Clinic Clinical Clinical Research Clinical Trials Clinical Trials Cooperative Group Communication Communities Crystal Formation Cystine Cystinuria Data Data Collection Decision Making Defect Diagnosis Diagnostic Diagnostic tests Disease Disease Progression Drug Metabolic Detoxication Education Elements End stage renal failure Enrollment Enzymes European Event Excision Excretory function Familiarity Family Figs - dietary Functional disorder Funding Future Generations Glyoxylates Goals Health Care Costs Hepatic Hepatocyte Hydroxypyruvate reductase Hyperoxaluria Impaired Renal Function Inborn Errors of Metabolism Individual Infection Inflammatory Inflammatory Response Inherited Injury Injury to Kidney Interdisciplinary Study International International Cooperation Intervention Investigation Joints Kidney Kidney Failure Kidney Transplantation Knowledge Lead Life Liver Longitudinal Studies Mediating Medical Meta-Analysis Metabolic Metabolic Pathway Minerals Minority Modeling Natural History Needs Assessment Nephrocalcinosis Nephrolithiasis Nephrology Obstruction Online Systems Operative Surgical Procedures Outcome Oxalates Pain Patient Care Patients Physicians Pilot Projects Play Prevalence Primary Hyperoxaluria Procedures Process Proteins Proteome Proximal Kidney Tubules Quality of Care Quality of life Rare Diseases Reaction Recurrence Registries Renal function Renal tubule structure Research Research Infrastructure Research Personnel Research Training Resource Sharing Resources Risk Salts Science Scientist Secure Severity of illness Site Structure Symptoms System Time Time Study Tissue Banking Tissue Banks Tissues Toxic effect Training Programs Transferase Treatment outcome United States National Institutes of Health Urinary Calculi Urinary tract Urine Urologist Woman Work adenine phosphoribosyltransferase advanced disease autosomal recessive trait clinical research site cohort disease-causing mutation disorder risk effective therapy efficacy testing experience glyoxylate hypercalciuria improved infancy inhibitor/antagonist investigator training kidney cell liver transplantation male meetings member men middle age multidisciplinary neuronal cell body patient advocacy group patient registry prevent programs public health relevance response solute success tissue resource treatment strategy urinary

项目摘要

DESCRIPTION (provided by applicant): 300 words Four inborn errors of metabolism lead to high concentrations of insoluble mineral salts in the urine and severe, recurrent nephrolithiasis. Patients with primary hyperoxaluria (PH), cystinuria, APRT deficiency (dihydroxyadeninuria, DMA), and Dent disease experience stones beginning in childhood. Deposition of crystals in kidney tissue and loss of kidney function is observed in all. Disease expression varies widely. Some PH patients, for example, progress to end stage renal failure during infancy, while others maintain kidney function until middle age. This variability is poorly understood. Modifiers of disease expression, if identified, offer promise as potential new treatment strategies. Yet progress toward effective treatment has been slow. Small numbers of widely scattered patients make rigorous characterization and longitudinal assessment of disease expression difficult. The ability to test efficacy of new treatments is limited since few patients are available for clinical trials. To address this problem, we will build on previous, successful work of the International Primary Hyperoxaluria Registry (IPHR) to expand the IPHR and establish secure, web-based registries and tissue banks for cystinuria, DHA, and Dent disease. Longitudinal studies of individual patients conducted in each disease will emphasize generation of testable hypotheses and identification of well characterized cohorts of patients for future clinical trials. All four diseases appear mediated by renal deposition of crystals, and the cellular response, which in turn, appears modulated by urinary protein inhibitors. Therefore, there is great potential for synergy to understand the impact of the urinary proteome and renal cell biology in disease progression. An outstanding consortium of clinical scientists with unique expertise and access to patient with these diagnoses will address this work. Multidisciplinary collaboration will occur through joint activities with the relevant patient support organizations, regular communications among Consortium members, and open sharing of newly developed resources with patients, members of the medical community and scientists. PUBLIC HEALTH RELEVANCE: The Consortium for Hereditary Causes of Nephrolithiasis and Renal Failure is highly suited to accomplish the characterization and longitudinal assessment needed to facilitate discovery of biomarkers of disease risk, disease activity, and response to therapy for four rare diseases that share similar mechanisms and severe disease manifestations. This work will address barriers of rare diseases research through vigorous multidisciplinary cooperation.

描述（由申请人提供）：300个单词的四个天生的新陈代谢误差导致尿液中高浓度的不溶性矿物质盐和严重的复发性肾石石症。原发性高黄油（pH），囊这尿症，APRT缺乏症（二羟基二肾内尿，DMA）和凹痕疾病的患者从童年开始经历结石。在肾脏组织中的晶体沉积和肾功能的丧失在所有人中都观察到。疾病表达差异很大。例如，一些pH患者在婴儿期终止肾衰竭，而另一些患者则保持肾脏功能直到中年。这种可变性知之甚少。疾病表达的修饰符（如果鉴定出来）将有望作为潜在的新疗法策略。然而，有效治疗的进展一直很慢。少数广泛分散的患者使疾病表达的严格表征和纵向评估困难。由于很少有患者可用于临床试验，因此测试新疗法功效的能力受到限制。为了解决这个问题，我们将建立在国际初级高黄油注册中心（IPHR）以前的成功工作，以扩大IPHR并为Cystinuria，DHA和DENTES疾病建立安全的，基于网络的注册表和组织库。对每种疾病进行的个别患者的纵向研究将强调产生可检验的假设，并鉴定出表征良好的患者同类群，以进行将来的临床试验。所有四种疾病似乎都是由晶体的肾脏沉积介导的，而细胞反应又是由尿蛋白抑制剂调节的。因此，协同作用有很大的潜力了解尿蛋白质组和肾细胞生物学对疾病进展的影响。具有独特专业知识和与患者使用这些诊断的临床科学家的杰出联盟将解决这项工作。多学科合作将通过与相关患者支持组织，财团成员之间的定期沟通以及与患者，医学界成员和科学家的新开发资源的公开共享进行多学科合作。公共卫生相关性：肾上腺素病和肾衰竭的遗传因素联盟非常适合完成所需的表征和纵向评估，以促进发现疾病风险，疾病活动的生物标志物，疾病活动的生物标志物以及对四种具有相似机制和严重疾病表现形式的疾病治疗的反应。这项工作将通过激烈的多学科合作解决罕见疾病研究的障碍。