A Metabolomic Approach to Discovering Biomarkers for ADPKD

描述(由申请人提供)： ADPKD是最常见的遗传性肾病，占终末期肾病人群的4%。利用肾脏成像检测肾囊肿是诊断本病最常见的方法，然而，由于受影响的人直到40岁才表现出肾囊性疾病，囊肿的出现往往被推迟。目前，除了基因分型外，还没有测试来诊断疾病的早期阶段，成功率只有85%。在这个修订的提案中，我们将利用代谢组学的新科学，与这一新兴领域的国际知名专家合作，发现作为ADPKD生物标志物的尿代谢物和血浆代谢物的模式。我们将利用正在进行的HALT研究中的患者材料；HALL首席调查员是这项研究的联合调查员。我们的合作生物统计学家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的初步数据计算了所需的样本量。我们的建议是非同寻常的，因为我们汇集了一支独特的研究队伍：一名细胞生物学家，同时也是临床科学家肾病学家(Weiss博士)，一名肾病学家和临床试验专家(Chapman博士)，一名蛋白质组和基因组学生物信息学专家(Perroud博士)，四名代谢组学专家(DRS Hammock、Grant、Michelmore和Fiehn)，以及一名在“组学”分析方面有专长的生物统计学家(Kim博士)，以利用代谢组学来解决一种相对常见的疾病的诊断和治疗问题，这种疾病很难诊断，目前的治疗选择有限。自最初提交以来，由于增加了更多的初步数据(包括人类对照试验和小鼠PKD代谢实验)，以及解决了原始审查者所有关切的叙述，包括解决关于对照数据解释的重要关切的新的具体目标，应用程序有了明显的改进。在PI的机构中，已经为这次修订招募了几名额外的代谢组学专家，他们与他保持着持续的科学关系，以帮助进行复杂的代谢数据解释，如果有必要的话。这些实验的成功完成将导致诊断方面的重大进步，并最终为这种疾病选择最佳治疗方案。我们将是第一个将代谢组学用于囊性肾脏疾病的描述，也是第一个在任何肾脏疾病中利用这项技术的人之一。此外，我们的工作可以作为使用代谢组学从各种遗传性疾病收集途径和网络数据的模型。 公共卫生相关性： ADPKD是最常见的遗传性肾病，占终末期肾病患者的4%。目前，除了基因分型只有85%的成功率，还没有测试来诊断这种疾病的早期、囊性前期阶段，在这个阶段，新的治疗方法具有最好的有效机会。该项目将导致在办公室进行简单的尿液和/或血液检测ADPKD，可用于初级保健、肾脏病和泌尿科诊所，从而使这种相对常见的疾病得到更早的治疗。此外，这项提案的工作将带来关于疾病病理的新知识，并选择将从任何新药中受益最大的患者。

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.