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ESRD人群的4%。肾囊肿的早期症状是什么？肾囊肿的早期症状是什么？目前，除了基因分型之外，没有任何测试可以在疾病的最早阶段进行诊断，并且只有85%的成功率。在这项修订后的提案中，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，发现尿液和血浆代谢物的模式，作为ADPKD的生物标志物。我们将使用正在进行的HALT研究的患者材料; HALT主要研究者是本研究的合作研究者。我们的合作生物统计学家利用来自我们两家机构的患者和对照的初步尿代谢组学分析的初步数据计算了所需的样本量。我们的提议非同寻常，因为我们召集了一批独特的调查人员：他是一位细胞生物学家，同时也是一位临床科学家兼肾病学家，（韦斯博士），肾病学家和临床试验专家（查普曼博士），蛋白质组学和基因组学生物信息学专家（Perroud博士），四位代谢组学专家（Hammock，Grant，Michelmore和Fiehn博士），以及一位擅长“组学”分析的生物统计学家利用代谢组学来解决诊断和治疗相对常见但难以诊断的疾病的问题，并且目前的治疗选择有限。自首次提交以来，通过添加更多初步数据（包括人类对照试验和小鼠PKD代谢组学实验）以及解决原始审查员所有问题的叙述（包括解决对照数据解释重要问题的新特定目的），该申请已得到显著改进。在PI所在机构招募了几名额外的代谢组学专家，他们与PI保持着持续的科学关系，如果有必要，他们将在此次修订中协助进行复杂的代谢组学数据解读。这些实验的成功完成将导致诊断的重大进展，并最终为这种疾病选择最佳治疗方案。我们的研究将是代谢组学在囊性肾病中的首次应用，也是第一个在任何肾脏疾病中利用这项技术的研究。此外，我们的工作可以作为一个模型，使用代谢组学收集途径和网络数据，从各种遗传性疾病。 公共卫生相关性： ADPKD是最常见的遗传性肾病，占ESRD人群的4%。目前，除了基因分型，这是成功的只有85%的时间，有没有测试，以诊断疾病的早期，前囊性阶段，在这个时候，新的治疗方法有最好的机会是有效的。该项目将导致一种简单的，基于办公室的尿液和/或血液检测ADPKD，可用于初级保健，肾脏病和泌尿科诊所，并将导致这种相对常见的疾病的早期治疗。此外，这项提案的工作将导致对疾病病理学的新认识，并选择将从任何新药中获益最多的患者。

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.