Advanced Methods in NMR-Based Metabolomics

描述（由申请人提供）：拟议的工作重点是开发用于代谢组学研究的核磁共振（NMR）光谱学先进方法。代谢组学领域的迅速发展提供了基于小分子代谢物信号的多种变化的生物扰动的新信息。NMR光谱学的新进展及其与质谱（MS）和多元统计方法的结合为许多生物学应用提供了有前途的方法，包括早期疾病诊断，治疗监测，药物开发和系统生物学的基础研究。虽然已知代谢组提供健康状态的瞬时快照，但由于生物样品中重叠信号的复杂性，健康和疾病的潜在生物标志物的鉴定和验证具有挑战性。在过去的几年里，我们已经开发了一套新的先进的NMR工具，可以用来解决这个问题，并承诺我们可以显着提高NMR的能力，解剖复杂的样品，并确定敏感和特定的代谢物生物标志物候选人。特别是，我们提出了三种先进的NMR方法，预计将提高10倍的检测限的代谢物在生物流体中，并增加NMR可检测的代谢物的数量由一个类似的因素。这一发展将改变目前基于NMR的代谢组学范式，并为目前基于MS的方法提供更强有力的补充。这些方法的验证一组商业血清样品和这些新方法的比较，目前的方法进行了讨论。如果这项工作取得成功，我们将为大大改进代谢组学研究奠定基础，其应用范围从早期疾病检测和治疗监测到系统生物学的基础研究。公共卫生相关性该项目旨在开发新的和先进的方法，用于识别血清和尿液样本中的疾病生物标志物。当这些方法得到充分发展时，可以用来检测血液或尿液中指示各种疾病发作的小分子。

DESCRIPTION (provided by applicant): The proposed work focuses on the development of advanced methods in nuclear magnetic resonance (NMR) spectroscopy for metabolomics-based studies. The rapidly expanding field of metabolomics provides new information on biological perturbations based on multiple changes in small molecule metabolite signals. New advances in NMR spectroscopy and their combination with mass spectrometry (MS) and multivariate statistical methods provide a promising approach for a number of biological applications including early disease diagnosis, treatment monitoring, drug development and basic investigations in systems biology. While the metabolome is known to provide an instantaneous snap-shot of health status, the identification and validation of potential biomarkers of health and disease is challenging due to the complexity of their overlapping signals in biological samples. Over the past several years, we have developed a new set of advanced NMR tools that can be brought to bear on this problem, with the promise that we can significantly increase the ability of NMR to dissect the complex samples and identify sensitive and specific metabolite biomarker candidates. In particular we propose three advanced NMR methods that are expected to improve the limit of detection of metabolites in biofluids by 10-fold and increase the number of NMR-detectible metabolites by a similar factor. This development would change the current paradigm in NMR-based metabolomics and provide an even stronger complement to current MS-based methods. Validation of these methods on a set of commercial serum samples and a comparison of these new approaches to current methods are also discussed. If this work is successful, we will have laid the foundation for much improved metabolomics studies for applications ranging from early disease detection and therapy monitoring to basic studies of systems biology. PUBLIC HEALTH RELEVANCE This project seeks to develop new and advanced methods for identifying biomarkers of disease in serum and urine samples. When fully developed these approaches could be used to detect small molecules in the blood or urine that indicate the onset of various diseases.