ADDING ADDITIONAL FUNDS UNDER OPTION PERIOD 1, TASK AREAS 5 AND 6, FOR CORE YEAR 5.

在选项期 1、任务领域 5 和 6 下为核心第 5 年添加额外资金。

基本信息

批准号：
10709463
负责人：
ASHLIN BOLTON
金额：
$ 874.58万
依托单位：
BROAD INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-28 至 2023-09-27
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10709463
关键词：
Address Affinity Antibodies Area Biochemical Biological Biological Assay Biological Markers Biological Models Cardiometabolic Disease Cardiovascular system Cohort Studies Collection Communities DNA Data Data Analyses Diabetes prevention Framingham Heart Study Funding Generations Genetic study Human Institutes Jackson Heart Study Label Laboratories Mass Spectrum Analysis Measures Methods National Heart, Lung, and Blood Institute Nucleotides Pathway interactions Pilot Projects Plasma Population Proteins Proteomics Protocols documentation Request for Proposals Research Personnel Resources Sampling Services Specificity Technology Time Tissue Sample Trans-Omics for Precision Medicine Validation Women&apos s Health Work aptamer base cohort database of Genotypes and Phenotypes experience genetic information interdisciplinary approach meetings metabolomics next generation sequencing novel novel marker population based programs response trait

项目摘要

The Broad will provide both metabolomics and proteomics service for the TOPMed. Metabolomics. Metabolomic technologies provide the systematic biochemical characterization of human plasma and tissue samples. We have established a high-throughput metabolomics platform that measures over 600 known metabolites based on authentic standards, as well as thousands of LC-MS peaks that we are methodically working to characterize. Our methods integrate both targeted and non-targeted LC-MS approaches. We have rigorously addressed intra- and interassay variability, acquiring data at “population” level scale. In prior analyses in the Framingham Heart Study (FHS), the Diabetes Prevention Study, the Women’s Health Initiative and other cohorts, we have identified novel biomarkers of cardiometabolic disease and integrated genetic information and studies in model systems to identify novel biologic pathways. In response to Task Order Request for Proposals issued in 2017 for pilot metabolomics studies on 2000 MESA samples and in 2018 for CORE Year 3 metabolite profiling of approximately 8000 samples, we provided high quality targeted and nontargeted data delivered in a complete and timely manner, meeting deadlines in both cases. We are presently collaborating with MESA investigators to generate metabolomics data on approximately 8000 plasma samples for Data generation for CORE Year 4. Since the pilot studies, we have been responsive to TOPMed investigators working with metabolomics data and have supported and collaborated on data analysis. Based on these experiences, we seek to provide metabolomic capabilities in response to Task Order Request for Proposal (TORFP) #75N92020R0034; Centralized Omics REsource (CORE); Task Area 5: Metabolite Profiles using our high throughput, multidisciplinary approach. Proteomics Emerging proteomic technologies are beginning to permit the systematic, unbiased characterization of human plasma samples, though few data exist in large, population-based cohort studies. To address limitations of prior studies, we have established a high-throughput proteomic platform in our laboratory that measures 1,536 proteins using an extensive collection of nucleotide-labeled antibodies (Olink). The assay leverages a novel method referred to as a proximity extension assay (PEA) which can be quantified by Next Generation Sequencing (NGS). We have rigorously addressed intra- and inter-assay variability (both <13%) and acquired data >20-fold faster than mass spectrometry based methods with a level of specificity that appears to be better than existing high throughput affinity-based methods that use DNA aptamers. In new work in the Jackson Heart Study and other cohorts, we confirmed established relationships between known biomarkers and cardiovascular traits and discovered many new associations. Based on these experiences, we seek to provide proteomic capabilities in response to Task Order Request for Proposal (TORFP) #75N92020R0034; Centralized Omics REsource (CORE); Task Area 6: Proteomics using our high throughput, multidisciplinary approach. Our proposal reflects a longstanding collaborative effort between our laboratory and the Broad Institute. The present application will also couple discovery with novel “orthogonal” validation protocols using mass spectrometry. All of the data generated on our platform will be available for TOPMed investigators and will be made broadly available in real time to the scientific community via dbGap, as we have done previously. We believe this body of experience strongly. supports our plan to analyze ~8,000 samples and provide proteomic profiles as part of the NHLBI TOPMed program in the coming year.

Broad将为顶级提供代谢组学和蛋白质组学服务。代谢组学。代谢组技术提供了人血浆和组织样品的系统生化表征。我们已经建立了一个高通量代谢组学平台基于真实标准的测量超过600种已知的代谢产物，以及我们有条不紊地努力表征的数千个LC-MS峰。我们的方法集成在一起靶向和非目标的LC-MS方法。我们已经严格解决了在“人口”级别上的收购数据，并获得了指体内和间的可变性。在弗雷明汉心脏研究（FHS）的先前分析中，糖尿病预防研究，妇女健康计划和其他同类群体，我们已经确定了心脏代谢疾病的新生物标志物以及模型系统中的综合遗传信息和综合遗传信息，以鉴定新的生物学途径。为了响应于2017年发布的有关2000 Mesa样本的试验代谢组学研究的提案请求，并在2018年针对大约8000个样本的核心3年级代谢物分析，我们提供了以完整和及时的方式提供的高质量目标和非目标数据。我们目前正在与MESA研究人员合作，以生成大约8000个血浆样本的代谢组学数据，以用于4年级的数据生成。由于试点研究，我们一直对使用代谢组学数据的最佳研究者有响应，并支持并协作了数据分析。根据这些经验，我们试图根据提案的任务订单请求（TORFP）＃75N9202020R0034提供代谢能力；集中式的OMICS资源（核心）；任务区域5：使用我们的高通量，多学科方法的代谢物概况。蛋白质组学新兴的蛋白质组学技术开始允许人类血浆样本的系统性，无偏见的表征，尽管在大型，基于人群的队列研究中很少存在数据。为了解决先前研究的局限核标记抗体（Olink）。该测定利用一种新方法称为接近扩展测定（PEA），可以通过下一代测序来量化（NGS）。我们已经严格解决了测定和测定间变异性（<13％），并且获得的数据比基于质谱的方法快20倍，具有特异性水平这似乎比使用使用DNA适体的现有高通量亲和力方法更好。在杰克逊心脏研究和其他人群的新作品中，我们确认了已知的生物标志物与心血管特征之间的既定关系，并发现了许多新的关联。根据这些经验，我们寻求根据提案的任务订单请求（TORFP）＃75N9202020R0034提供蛋白质组学能力；集中式的OMICS资源（核心）；任务区域6：使用我们的高通量，多学科方法的蛋白质组学。我们的建议反映了我们的实验室与广泛研究所之间的长期合作努力。本应用程序还将使用质谱法与新颖的“正交”验证方案进行逐步发现。我们平台上生成的所有数据都将用于顶级研究人员，并将通过DBGAP实时向科学界实时提供，就像我们之前所做的那样。我们相信这种经验很强。支持我们分析约8,000个样本并提供蛋白质组学概况的计划，这是来年NHLBI顶级计划的一部分。