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。

• 批准号: 10510183
• 负责人: ASHLIN BOLTON
• 金额: $ 1095.33万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-28 至 2022-09-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10510183
• 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' 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

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.

博德将为TOPMed提供代谢组学和蛋白质组学服务。 代谢组学。 代谢组学技术提供了人体血浆和组织样本的系统生化特征。我们已经建立了一个高通量的代谢组学平台 根据可靠的标准测量600多种已知代谢物，以及我们正在有条不紊地工作的数千个LC-MS峰。我们的方法将两者结合在一起 定向和非定向LC-MS方法。我们已经严格地处理了化验内和化验间的可变性，获取了“总体”水平的数据。在弗雷明翰心脏研究(FHS)、糖尿病预防研究、妇女健康倡议和其他队列的先前分析中，我们已经确定了心脏代谢性疾病的新生物标记物，并整合了遗传信息和模型系统中的研究，以确定新的生物途径。针对2017年发布的关于2000个MESA样本的代谢组学试点研究的建议和2018年针对大约8000个样本的第3年核心代谢物分析的建议的任务单请求，我们提供了高质量的、有针对性的和非有针对性的数据，以完整和及时的方式提供，在这两种情况下都满足了最后期限。我们目前正在与MESA研究人员合作，在大约8000个血浆样本上生成代谢组学数据，以用于核心年份的数据生成。自试点研究以来，我们一直响应TOPMed研究人员处理代谢组学数据的工作，并在数据分析方面提供支持和合作。基于这些经验，我们寻求提供代谢能力，以响应任务订单征求建议书(TORFP)#75N92020R0034；集中式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对人类血浆样本进行系统的、公正的表征，尽管在大规模的基于人群的队列研究中几乎没有数据。为了解决先前研究的局限性，我们在实验室建立了一个高通量蛋白质组平台，使用广泛的收集来测量1536个蛋白质 核苷酸标记抗体(Olink)。该分析利用了一种被称为邻近延伸分析(PEA)的新方法，该方法可以通过下一代测序进行量化 (NGS)。我们严格处理了检测内和检测间的可变性(均为13%)，获得的数据比基于质谱学的方法快20倍，且具有一定的特异性 这似乎比现有的使用DNA适配子的高通量亲和力方法更好。在杰克逊心脏研究和其他队列的新工作中，我们证实了已知生物标记物和心血管特征之间已建立的关系，并发现了许多新的关联。基于这些经验，我们寻求提供蛋白质组能力，以响应任务订单征求建议书(TORFP)#75N92020R0034；集中式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和布罗德研究所之间的长期合作努力。本申请还将利用质谱学将发现与新颖的“正交”验证方案相结合。我们平台上产生的所有数据将供TOPMed调查人员使用，并将通过DBGaP向科学界广泛实时提供，就像我们以前所做的那样。我们强烈地相信这一经验。支持我们在来年分析约8,000个样本并提供蛋白质组图谱的计划，作为NHLBI TOPMed计划的一部分。