Plasma proteomics in CHS and population biology

CHS 和群体生物学中的血浆蛋白质组学

• 批准号: 9815869
• 负责人: ROBERT E GERSZTEN
• 金额: $ 179.99万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9815869
• 关键词: Aging; Atrial Fibrillation; Biological; Biological Assay; Biological Markers; Biological Process; Biological Response Modifier Therapy; Biology; Cardiovascular Diseases; Cardiovascular system; Chronic Disease; Clinical; Clinical Medicine; Clinical Research; Cohort Analysis; Cohort Studies; Collaborations; Coronary heart disease; Data; Diabetes Mellitus; Disease; Drug Targeting; Elderly; Enzyme-Linked Immunosorbent Assay; Epidemiology; Etiology; Evaluation; FDA approved; Framingham Heart Study; Funding; Genetic; Genetic Determinism; Genetic Risk; Genomics; Goals; Grant; Group Structure; Health; Health Status; Heart; Heart failure; Human; Incentives; Incidence; Individual; Jackson Heart Study; Kidney; Kidney Diseases; Knowledge; LDL Cholesterol Lipoproteins; Lead; Letters; Low-Density Lipoproteins; Lung; Mass Spectrum Analysis; Measures; Methods; Modeling; Molecular Target; Monoclonal Antibodies; Neurologic; Outcome; Participant; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Plasma; Plasma Proteins; Population; Population Biology; Population Sciences; Prevention; Prospective cohort; Proteins; Proteomics; Publications; Quality Control; Randomized; Relative Risks; Renal Glycosuria; Research; Research Personnel; Risk; Robotics; Safety; Sample Size; Sampling; Science; Scientist; Stroke; Sudden Death; Techniques; Technology; Trans-Omics for Precision Medicine; Validation; Variant; aptamer; base; bone; cardiovascular health; career; cohort; disorder subtype; experience; frailty; genetic association; genetic variant; genome wide association study; genomic epidemiology; human disease; improved; inhibitor/antagonist; insight; interest; member; new therapeutic target; novel; novel therapeutics; study population; targeted treatment; whole genome; working group

In studies of cardiovascular disease and aging, the emergence of various types of omics data has transformed population science. In the last decade, for instance, genome-wide association studies (GWAS) have identified and replicated thousands of genetic associations with measures of health and disease. Their primary contribution has been an improvement in the understanding of the etiology of a variety of health conditions—human population biology. These discovery efforts can lead rapidly to new therapies such as the PCSK9 inhibitors. Likewise, proteomics can advance our understanding of biology. Proteins perform most biological functions, and they are often not only the target of drug therapies, but also key biomarkers in clinical medicine. Recent advances in technology have improved multiplexed protein assays and made large scale studies in humans tractable. In the proposed project, we plan to assay 1310 plasma proteins in 3200 Cardiovascular Health Study (CHS) participants with an aptamer-based method, one that has high sensitivity for low-abundance proteins and high throughput for a large number of samples. A cohort study of older adults, CHS currently provides active support, including central analysis, for eight phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 junior or mid-career scientists. With experience in genomics and a funded WG model, CHS is well-organized to take advantage of novel large- scale phenotyping techniques such as proteomics to advance knowledge of human health and disease. The goal of the project is to use proteomics to improve our understanding of disease etiology and prevention in older adults. The primary hypotheses involve an evaluation of associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses in CHS. The plans are to release the protein-assay results immediately to the eight CHS WGs and their 115 investigators, to provide central analytic support to the WGs, to offer mass-spectrometry-based validation of selected proteins, and to leverage opportunities for replication in the Framingham Heart Study and Jackson Heart Study. Multiple forms of genetic data, including whole-genome sequence data, are also available to verify the identity of proteins and to establish their genetic determinants. In addition, Mendelian randomization analyses will be used to examine supportive evidence for causal associations between protein levels and health outcomes. For key proteins, new ELISA assays will be developed for additional clinical research. The significance of this proposal lies in the combined strengths of the well-phenotyped cohort of older adults, the rigorously validated proteomic technique, the available genetic data, the WG structure, the central support for analysis, the assay validation efforts, the replication plans, the productive CHS WG members, and the data-sharing plans.

在心血管疾病和衰老的研究中，各种类型的OMICS数据的出现具有 转变的人口科学。例如，在过去的十年中，全基因组关联研究（GWAS） 已经确定并复制了成千上万的遗传关联与健康和疾病的衡量标准。他们的 主要贡献是对各种健康的病因的理解的改善 条件 - 人口生物学。这些发现的努力可能会迅速导致新疗法 PCSK9抑制剂。同样，蛋白质组学可以提高我们对生物学的理解。蛋白质执行 大多数生物学功能，它们通常不仅是药物疗法的靶标，而且是关键的生物标志物 临床医学。技术的最新进展改善了多路复用蛋白质分析并进行了 人类的大规模研究。 在拟议的项目中，我们计划在3200个心血管健康研究中分析1310血浆蛋白 （CHS）具有基于合并的方法的参与者，该方法对低丰度蛋白具有高灵敏度 和大量样品的高吞吐量。 CHS目前提供的一项老年人的队列研究 对八个表型特异性工作组（WGS）的主动支持，包括中央分析。每个CHS WG由一两个高级调查员领导，包括10至20名初级或中级科学家。和 CHS具有基因组学和资助的WG模型的经验，可以充分利用新型的大型大型 比例表型技术，例如蛋白质组学，以提高人们对人类健康和疾病的了解。 该项目的目的是使用蛋白质组学来提高我们对疾病病因的理解和 老年人的预防。主要假设涉及对基线之间关联的评估 循环蛋白的水平以及前瞻性队列中各种健康结果的事件 CHS分析。这些计划是将蛋白质测定结果立即发布到八个CHS WG和 他们的115名调查人员为WG提供了中央分析支持，以提供基于质谱的测量值 验证选定的蛋白质，并利用弗雷明汉心脏研究中的复制机会 和杰克逊心脏学习。多种形式的遗传数据，包括全基因组序列数据，也是 可用于验证蛋白质的身份并确定其遗传决定剂。此外，门德利安 随机分析将用于检查有关因果关系的支持证据 蛋白质水平和健康结果。对于关键蛋白质，将开发新的ELISA分析以供其他 临床研究。该提议的重要性在于良好的型号的综合优势 老年人队列，严格验证的蛋白质组学技术，可用的遗传数据，WG 结构，分析的中心支持，测定验证工作，复制计划，产品 CHS WG成员和数据共享计划。