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：
9279037
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/9279037
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 health clinical phenotype cognitive function cohort disability disorder risk effective therapy experimental study follow-up hemodynamics improved innovation liquid chromatography mass spectrometry member mortality muscle regeneration 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（由适用提供）：我们建议测试小鼠实验是否表明循环蛋白可以在大脑，心脏和骨骼肌中恢复或加速衰老，转化为与老年人重要临床结果的相应关联。我们使用对GDF11的测定法进行了测量以测量其紧密的结构同源物GDF8，我们在初步研究中证明了这些Geronic蛋白与患有患有普遍的冠状动脉疾病的队列中的入射心力衰竭（HF）和动脉粥样硬化心血管疾病（ASCVD）有关。相比之下，GDF11和GDF8的拮抗剂Follistatin样3暴露了相反的关联。这些发现凸显了需要识别更具体测定的必要一般基于人群的同伙的途径。因此，我们将对最先进的LC质谱，基于APATMER的蛋白质组学和免疫测定法进行系统比较，以选择每种蛋白质的最佳测定法。然后，我们将利用两个大型混血儿同伙，心血管健康研究和健康衰老和身体成分研究的全面临床表型和特殊的统计能力，以有效地测试以下假设。首先，降低小鼠神经发生的CCL11和ß2微球蛋白的较高水平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与左心室较低（LV）质量以及心力衰竭的风险降低有关，尤其是在保留的射血分数（HFPEF），ASCVD和痴呆症风险的情况下。第三，较高水平的GDF11和氧化的肌肉强度以及降低了活动能力的风险。除了这些终点之外，我们还将研究各种不良结果。此外，我们将使用巴尔的摩纵向衰老纵向研究的数据和标本来描述这些蛋白质的水平如何在20至96岁之间变化。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，LV质量和肌肉强度。拟议的研究将由PIS的协调团队和研究人员领导，他们是实验室科学，老年医学，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。抛物线率和这些蛋白质的基本生物学领导者的杰出科学顾问委员会已经并且将继续为我们对宠物和表型的选择提供信息，并指导我们数据的分析。因此，拟议的研究将对人类人群中的这些令人兴奋的蛋白质进行全面分析，目的是确定新型的治疗靶标的是残疾和死亡的主要原因目前很少有有效的治疗方法。