A Metabolomic Approach to Discovering Biomarkers for ADPKD

发现 ADPKD 生物标志物的代谢组学方法

• 批准号: 7731766
• 负责人: ROBERT H. WEISS
• 金额: $ 35万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-17 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7731766
• 关键词: Accounting; Address; Affect; Age; Appearance; Autosomal Dominant Polycystic Kidney; Biochemical; Bioinformatics; Biological Markers; Blood Tests; Cells; Circadian Rhythms; Clinic; Clinical; Clinical Trials; Collaborations; Critiques; Cyst; Cystic Kidney Diseases; Cystic kidney; Data; Detection; Diagnosis; Diagnostic tests; Dietary Sodium; Disease; Disease Progression; Early Diagnosis; Early treatment; End stage renal failure; Gender; Genomics; Genotype; Glean; Grant; Hereditary Disease; Human; Image; Individual; Inherited; Institution; Intake; Kidney; Kidney Diseases; Knowledge; Lead; Life; Metabolic; Metabolic Pathway; Methods; Modeling; Mus; Nephrology; Pathology; Pathway Analysis; Pathway interactions; Patient Selection; Patients; Pattern; Pharmaceutical Preparations; Plasma; Population; Potassium; Primary Health Care; Principal Investigator; Proteins; Proteomics; Publishing; Recruitment Activity; Renal function; Research Personnel; Role; Sample Size; Science; Scientist; Serum; Severity of illness; Staging; Technology; Testing; Time; Treatment Protocols; Urine; Urology; Work; base; control trial; design; disease diagnosis; improved; metabolomics; novel; novel therapeutics; public health relevance; research study; urinary

DESCRIPTION (provided by applicant): ADPKD is the most prevalent inherited renal disease, accounting for 4% of the ESRD population. Detection of renal cysts utilizing renal imaging has been the most common method of diagnosis of this disease however, cyst appearance is often delayed with affected individuals not demonstrating renal cystic disease until the 4th decade of life. At present, other than genotyping, there is no test to diagnose the disease in its earliest stages and is successful only 85% of the time. In this revised proposal, we will exploit the new science of metabolomics, in collaboration with internationally-renowned experts in this nascent field, to discover a pattern of urinary and plasma metabolites which serve as biomarkers for ADPKD. We will utilize patient materials from the ongoing HALT study; a HALT Principal Investigator is the co-Investigator for this study. Our collaborating biostatistician has calculated the desired sample size utilizing preliminary data derived from preliminary urinary metabolomic analysis of patients and controls from our two institutions. Our proposal is extraordinary in that we have assembled a unique cadre of investigators: a cell biologist who is also a clinician-scientist nephrologist (Dr. Weiss), a nephrologist and clinical trials expert (Dr. Chapman), a proteomics and genomics bioinformatics expert (Dr. Perroud), four metabolomics experts (Drs Hammock, Grant, Michelmore and Fiehn), and a biostatistician with expertise in "omic" analyses (Dr. Kim) to utilize metabolomics to tackle the problem of diagnosis and treatment of a relatively common disease which is difficult to diagnose, and for which current treatment options are limited. The application has been markedly improved since the original submission by the addition of more preliminary data (including a human control trial and a mouse PKD metabolomic experiment), as well as narrative which addresses all of the concerns of the original reviewers including a new Specific Aim which addresses important concerns about control data interpretation. Several additional metabolomics experts at the PI's institution, with whom he has ongoing scientific relationships, have been recruited for this revision to assist in complicated metabolomic data interpretation, should this become necessary. Successful completion of these experiments will result in a major advance in diagnosis as well as, ultimately, the selection of optimal treatment regimens for this disease. Ours will be the first described use of metabolomics in cystic kidney disease, and one of the first to exploit this technology in any renal disease. Furthermore, our work can serve as a model for using metabolomics to glean pathway and network data from a variety of hereditary diseases. PUBLIC HEALTH RELEVANCE: NARRATIVE ADPKD is the most prevalent inherited renal disease accounting for 4% of the ESRD population. At present, other than genotyping, which is successful only 85% of the time, there is no test to diagnose the disease in its early, pre-cystic stages at which time novel therapies have the best chance of being effective. This project will lead to a simple, office-based urine and/or blood test for detection of ADPKD, which can be utilized in the primary care, nephrology, and urology clinics and which will lead to earlier treatment of this relatively common disease. In addition, work from this proposal will lead to new knowledge about the pathology of the disease and to selection of patients who will most benefit from any new drug.

描述（由申请人提供）： ADPKD是最普遍的继承肾脏疾病，占ESRD人群的4％。利用肾脏成像的肾脏囊肿的检测一直是该疾病诊断的最常见方法，但是，直到生命的第四个十年，受影响的个体通常会延迟囊肿的外观。目前，除了基因分型外，还没有测试在最早的阶段诊断该疾病，并且仅在85％的时间内成功地诊断了该疾病。在这项修订的提案中，我们将与这个新生领域的国际知名专家合作利用新的代谢组学科学，以发现一种尿和血浆代谢物的模式，这些模式是ADPKD的生物标志物。我们将利用正在进行的停止研究中的患者材料；停止的首席研究员是本研究的共同投资者。我们的合作生物统计学家计算了利用来自我们两个机构的患者和对照的初步尿代谢组分析得出的初步数据所需的样本量。 Our proposal is extraordinary in that we have assembled a unique cadre of investigators: a cell biologist who is also a clinician-scientist nephrologist (Dr. Weiss), a nephrologist and clinical trials expert (Dr. Chapman), a proteomics and genomics bioinformatics expert (Dr. Perroud), four metabolomics experts (Drs Hammock, Grant, Michelmore and Fiehn), and a具有“ OMIC”分析（KIM博士）专业知识的生物统计学家利用代谢组学来解决相对常见疾病的诊断和治疗问题，这很难诊断，并且目前的治疗方案受到限制。自从原始提交以来，通过添加更多初步数据（包括人类控制试验和小鼠PKD代谢组实验）以及叙述，该应用程序已得到明显改进，并叙述了针对原始审阅者的所有担忧，包括新的特定目标，该目标解决了有关控制数据解释的重要问题。如果有必要，请招募PI机构的几位代谢组学专家，与他持续的科学关系进行了招募，以协助复杂的代谢数据解释。这些实验的成功完成将导致诊断的重大进展，并最终为该疾病选择最佳治疗方案。我们的将是对囊性肾脏疾病中最早描述的代谢组学的使用，也是最早在任何肾脏疾病中利用这项技术的一种。此外，我们的工作可以作为使用代谢组学收集途径和来自各种遗传性疾病的网络数据的模型。 公共卫生相关性： 叙事ADPKD是占ESRD人群4％的最普遍的遗传肾脏疾病。目前，除了仅在85％的时间成功的基因分型外，还没有进行诊断疾病的早期，囊性阶段的测试，而新型疗法最有效的机会。该项目将导致简单的基于办公室的尿液和/或血液检查以检测ADPKD，可用于初级保健，肾脏病和泌尿外科诊所，并将导致这种相对常见的疾病的早期治疗。此外，该提案的工作将导致有关该疾病病理学的新知识，并选择最能从任何新药中受益的患者。