Relationship of candidate circulating proteoforms with aging phenotypes.

候选循环蛋白型与衰老表型的关系。

• 批准号: 9248089
• 负责人: RICHARD D SEMBA
• 金额: $ 21.06万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248089
• 关键词: 21 year old; Activities of Daily Living; Address; Adult; Affect; Age; Aging; Animal Model; Animals; Attention; Baltimore; Binding; Biological; Biological Assay; Blood; C-terminal; Carrier Proteins; Cleaved cell; Cognition; Conflict (Psychology); Development; Eotaxin; Epitopes; Follistatin; Follistatin-Like Protein 3; GDF11 gene; GDF8 gene; Genes; Health; Heart Hypertrophy; Human; Immunoassay; Insulin Resistance; Liquid Chromatography; Longitudinal Studies; Lower Extremity; Measures; Memory; Molecular; Monitor; Muscle; Oxytocin; Peptides; Phenotype; Physical Performance; Plasma; Post-Translational Protein Processing; Protein Isoforms; Proteins; Public Health; Reaction; Reagent; Rejuvenation; Reporting; Research; Research Design; Role; Skeletal Muscle; Stable Isotope Labeling; Technology; Testing; Validation; Walking; age related; aged; cohort; disability; growth-differentiation factor 8; inhibitor/antagonist; innovation; muscle form; muscle strength; neurophysins; novel; polypeptide; sarcopenia; secondary outcome; skeletal muscle growth; tandem mass spectrometry; therapeutic target; walking speed

 DESCRIPTION (provided by applicant): Recent animal studies have identified several polypeptides or proteins that can reverse or accelerate aging phenotypes. These candidates include growth/differentiation factor 11 (GDF11), growth/differentiation factor 8 (GDF8), oxytocin, eotaxin, and inhibitors of GDF11 and GDF8: GDF11 and GDF8 propeptides, follistatin, follistatin-related protein 3 (FSTR3), WFIKKN1, and WFIKKN2. These candidate polypeptides or proteins have been difficult to study in the blood using conventional immunoassays, since some of the peptides or proteins exist in multiple isoforms, undergo cleavage or terminal degradation, or have high sequence identity with each other. Whether these proteoforms (defined as the different molecular forms in which the protein product of a single gene can be found, such as isoforms, cleavage, and degradation products) have a similar relationship to aging phenotypes in humans is not known. We will use a novel multiplexed selected reaction monitoring (SRM) assay and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure fifteen plasma proteoforms representing eight important proteins in rejuvenation research. We will test the hypothesis that plasma concentrations of these candidate proteoforms change with aging, and, beyond chronological age, predict the development of specific aging phenotypes in adults. The specific aims are: (1) to finalize development of the SRM assay using LC-MS/MS for absolute quantification of plasma proteoforms: GDF11 (propeptide, mature protein), GDF8 (propeptide, mature protein), follistatin (2 isoforms, 1 cleaved form), FSTR3, WFIKKN1, WFIKKN2, eotaxin, oxytocin (nonapeptide, 2 carboxyl-extended forms) and its carrier protein, neurophysin-1, (2) to characterize the relationship of circulating candidate proteoforms with aging phenotypes in the Baltimore Longitudinal Study of Aging and in a replication cohort, the InCHIANTI Study. Aging phenotypes include prevalent and incident sarcopenia, lower extremity physical performance, disability, cognition, memory, cardiac hypertrophy, and insulin resistance. By the end of the project, we should be able to verify or refute the role of these candidate proteoforms in phenotypes of human aging.

 描述（由适用提供）：最近的动物研究确定了几种可以逆转或加速衰老表型的多肽或蛋白质。这些候选者包括生长/分化因子11（GDF11），GDF11和GDF8的生长/分化因子8（GDF8），氧气，eotaxin和GDF8：GDF11和GDF8丙肽，Follistatin，Follistatin，Follistatin，与Follistatin相关的蛋白3（FSTR3），WFIKKN1，WFIKKN1和WFIKKN2。这些候选多肽或蛋白质很难在血液中使用常规免疫测定法研究，因为某些肽或蛋白质存在于多种同工型中，经历了裂解或末端降解，或者彼此具有高序列同一性。这些蛋白质成型（定义为可以找到单个基因蛋白质产物的不同分子形式，例如同工型，裂解和降解产物）与人类在人类衰老表型的关系类似。我们将使用新型的多重反应监测（SRM）测定法和液相色谱串联质谱法（LC-MS/MS）来测量代表八种改革研究中的八种重要蛋白质的15个血浆蛋白质成型。我们将检验以下假设：这些候选蛋白成型成型的血浆浓度随着年龄的增长而变化，并且超出了年龄，还可以预测成年人特定衰老表型的发展。 The specific aims are: (1) to finalize development of the SRM assay using LC-MS/MS for absolute quantification of plasma proteinoforms: GDF11 (propeptide, mature protein), GDF8 (propeptide, mature protein), follistatin (2 isoforms, 1 cleaved form), FSTR3, WFIKKN1, WFIKKN2, eotaxin, oxytocin （非肽，2种羧基延伸的形式）及其载体蛋白神经蛋白1，（2），以表征巴尔的摩衰老纵向研究和复制队列中循环候选蛋白基础与衰老表型的关系，Inchianti研究。衰老的表型包括普遍的和事件的肌肉减少症，下肢身体性能，残疾，认知，记忆，心脏肥大和胰岛素抵抗。到项目结束时，我们应该能够验证或反驳这些候选蛋白质成型在人类衰老表型中的作用。