Comprehensive Evaluation of Aging-Related Clinical Outcomes and Geroproteins

衰老相关临床结果和Gero蛋白的综合评价

• 批准号: 9519838
• 负责人: STEVEN RON CUMMINGS
• 金额: $ 63.5万
• 依托单位: CALIFORNIA PACIFIC MED CTR RES INSTITUTE
• 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 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9519838
• 关键词: ART protein; Adult; Adverse effects; Age; Aging; Anemia; Atherosclerosis; Baltimore; Biological Assay; Biology; Biometry; Blood Vessels; Body Composition; Brain; CCL11 gene; Cardiology; Cardiovascular Diseases; Cause of Death; Cessation of life; Clinical; Cognition; Cognitive; Colon Carcinoma; Communities; Coronary heart disease; Data; Dementia; Diagnosis; EFRAC; Elderly; Enzyme-Linked Immunosorbent Assay; Epidemiologic Methods; Erythropoiesis; Evaluation; Exhibits; FSTL3 gene; Family; Follistatin; GDF11 gene; GDF8 gene; General Population; Geriatrics; Goals; Growth and Development function; Health; Heart Hypertrophy; Heart failure; Homologous Gene; Hormones; Hospitalization; Human; Immunoassay; Impaired cognition; Inflammatory Response; Injury; Investigation; Laboratories; Left Ventricular Mass; Longevity; Longitudinal Studies; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Memory; Mus; Muscle; Myocardium; Natural regeneration; Neurology; Outcome; Oxytocin; Parabiosis; Pathway interactions; Pattern; Peptides; Phenotype; Physiological; Play; Proteins; Proteomics; Protocols documentation; Race; Reporting; Research Personnel; Risk; Role; Science; Skeletal Muscle; Smell Perception; Specific qualifier value; Specificity; Specimen; Testing; Tissues; Transforming Growth Factor beta; Translating; Variant; adverse outcome; age related; aptamer; base; beta-2 Microglobulin; biracial; cardiovascular disorder risk; cardiovascular health; clinical phenotype; cognitive function; cohort; disability; effective therapy; experimental study; follow-up; hemodynamics; improved; innovation; liquid chromatography mass spectrometry; member; mortality; muscle strength; neurogenesis; new therapeutic target; population based; psychologic; public health relevance; reproductive; sex; young adult

 DESCRIPTION (provided by applicant): We propose to test whether mouse experiments showing that circulating proteins can rejuvenate or accelerate aging in the brain, heart, and skeletal muscle translate into corresponding associations with important clinical outcomes in older adults. Using an assay for GDF11 that has since been determined also to measure its close structural homologue, GDF8, we demonstrated in preliminary studies that these geronic proteins are associated with incident heart failure (HF) and atherosclerotic cardiovascular disease (ASCVD) in cohorts with prevalent coronary disease. By contrast, follistatin-like 3, an antagonist of GDF11 and GDF8, exhibited the opposite associations. These findings highlight the need to identify more specific assays, and they also call for broader investigation of relevant pathways in general population-based cohorts. We will therefore undertake systematic comparisons of state-of-the-art LC mass spectroscopy, aptamer-based proteomics, and immunoassays to select the best assay for each protein. We will then harness the comprehensive clinical phenotyping and exceptional statistical power of two large, biracial cohorts, the Cardiovascular Health Study and the Health Aging, and Body Composition Study to efficiently test the following hypotheses. First, that higher levels of CCL11 and of ß2 microglobulin, which decrease neurogenesis in mice, are associated with impaired cognitive function and increased risk of dementia. Second, that as in mice, higher levels of GDF11 are associated with lower left ventricular (LV) mass and reduced risk of heart failure, particularly with preserved ejection fraction (HFpEF), ASCVD, and risk of dementia. Third, that higher levels of GDF11 and oxytocin are associated with improved skeletal muscle strength and reduced risk of mobility disability. Beyond these endpoints, we will also examine various adverse outcomes. Moreover, we will describe how levels of these proteins vary across the lifespan, from age 20 to 96, using data and specimens from the Baltimore Longitudinal Study of Aging. These data will enable us to analyze how levels of these proteins influence cognition, LV mass, and muscle strength across the life span. The proposed study will be led by a coordinated team of PIs and investigators who are leaders in their fields of laboratory science, geriatrics, cardiology, neurology, muscle and mobility, and biostatistics. An exceptional Scientific Advisory board of leaders in parabiosis and the basic biology of these proteins has and will continue to inform our choices of peptides and phenotypes, and guide analyses of our data. Hence, the proposed study will provide a comprehensive analysis of these exciting proteins in human cohorts with the aim of identifying novel therapeutic targets for major causes of disability and mortality for which few effective treatments are currently available.

 描述（由申请人提供）：我们建议测试小鼠实验是否表明循环蛋白可以使大脑、心脏和骨骼肌恢复活力或加速衰老，从而转化为与老年人重要临床结果的相应关联。使用 GDF11 检测（此后也确定可以测量其紧密结构同源物 GDF8），我们在初步研究中证明，这些老年蛋白与流行冠心病人群中的心力衰竭 (HF) 和动脉粥样硬化性心血管疾病 (ASCVD) 相关。相比之下，卵泡抑素样 3（GDF11 和 GDF8 的拮抗剂）表现出相反的关联。这些发现强调需要确定更具体的检测方法，并且还呼吁对相关的进行更广泛的调查 以一般人群为基础的队列中的途径。因此，我们将对最先进的 LC 质谱、基于适体的蛋白质组学和免疫分析进行系统比较，以选择每种蛋白质的最佳分析方法。然后，我们将利用心血管健康研究和健康老龄化和身体成分研究这两个大型混血儿队列的综合临床表型和卓越的统计能力来有效地检验以下假设。首先，较高水平的 CCL11 和 ß2 微球蛋白会减少小鼠的神经发生，与认知功能受损和痴呆风险增加有关。其次，与小鼠一样，较高水平的 GDF11 与较低的左心室 (LV) 质量和心力衰竭风险降低相关，特别是与射血分数保留 (HFpEF)、ASCVD 和痴呆风险降低相关。第三，较高水平的 GDF11 和催产素与骨骼肌力量的提高和行动障碍风险的降低相关。除了这些终点之外，我们还将检查各种不良后果。此外，我们将使用巴尔的摩纵向衰老研究的数据和样本来描述这些蛋白质的水平在从 20 岁到 96 岁的整个生命周期中如何变化。这些数据将使我们能够分析这些蛋白质的水平如何影响整个生命周期的认知、左心室质量和肌肉力量。拟议的研究将由一个由 PI 和研究人员组成的协调团队领导，他们是实验室科学、老年病学、心脏病学、神经病学、肌肉和流动性以及生物统计学领域的领导者。由联体共生和这些蛋白质的基础生物学领域的领导者组成的杰出科学咨询委员会已经并将继续为我们选择肽和表型提供信息，并指导我们的数据分析。因此，拟议的研究将对人类队列中这些令人兴奋的蛋白质进行全面分析，旨在针对残疾和死亡的主要原因确定新的治疗靶点，其中 目前有效的治疗方法很少。