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

基本信息

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
项目类别：
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

项目摘要

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）：我们建议使用 GDF11 检测来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。此后也被确定测量其密切的结构同源物 GDF8，我们在初步研究中证明这些老年蛋白与队列中的心力衰竭 (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）显示出相反的关联。这些发现强调需要确定更具体的检测方法，并且还需要对相关的进行更广泛的研究。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，以便为每种蛋白质选择最佳分析方法。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群体的卓越统计能力有效地检验了以下假设：首先，CCL11 和 CCL11 的水平较高。 β2 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 与左心室 (LV) 质量降低和心力衰竭风险降低相关，尤其是。第三，较高水平的 GDF11 和催产素与改善骨骼肌力量和降低行动障碍风险有关。此外，我们还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进行分析。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这项拟议的研究将由实验室科学、老年医学、心脏病学等领域的领导者和研究人员组成的协调小组领导。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顾问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。将对人类队列中这些令人兴奋的蛋白质进行全面分析，旨在针对导致残疾和死亡的主要原因确定新的治疗靶点目前有效的治疗方法很少。