MtDNA variant modifiers of cardiopulmonary responsiveness to physical activity

体力活动心肺反应性的线粒体 DNA 变异修饰剂

基本信息

批准号：
8791272
负责人：
Carlos A. Vaz Fragoso
金额：
$ 27.36万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-15 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8791272
关键词：
Address Adherence Adult Aerobic Aerobic Exercise Age Aging American Americas Ancillary Study Attention Behavior Behavior Therapy Behavioral Genetics Blood Pressure Body Weight Cardiopulmonary Cardiovascular Diseases Cardiovascular system Chronic Clinical Code Communities Complex Control Groups DNA Sequence Data Databases Dementia Development Diastolic blood pressure Elderly Electron Transport Energy Metabolism Enzymes Ethnic Origin Event Exercise Family Study Fatigue Foundations Genes Genetic Genetic Fingerprintings Genetic Materials Genetic Variation Genomics Goals Health Health Status Health education Heterogeneity Individual Inherited International Intervention Knowledge Lead Life Expectancy Lipids Lung Lung Capacity Masks Measures Mental Depression Mitochondrial DNA Modeling Molecular Movement Nuclear Observational Study Outcome Participant Pathway interactions Pattern Persons Pharmacotherapy Phase Physical Fitness Physical activity Physically Handicapped Pilot Projects Play Population Prevalence Procedures Public Health Publications Quality of life Race Randomized Randomized Controlled Trials Recommendation Research Respiratory physiology Risk Role Sampling Sleep Speed Spirometry Systolic Pressure Testing Time Variant Walking Work age related aged authority base blood glucose regulation cardiovascular health cohort comparative efficacy cost design fitness follow-up gene discovery genetic makeup genetic variant high risk improved improved mobility innovation insight lifestyle intervention meter muscle strength new therapeutic target novel personalized medicine programs response sedentary sedentary lifestyle sex trial comparing

项目摘要

DESCRIPTION (provided by applicant): The prevalence of cardiovascular disease will rise as life expectancy of older Americans continues to increase, with persons aged >75 years representing the fastest growing segment of the US population. Poor physical fitness is a major contributor to poor cardiopulmonary function that is primarily caused by a sedentary lifestyle. Increasing physical activity remains a priority for improving cardiovascular health, especially in older adults, who are at the greatest risk of chronic health conditions. While it is generally recognized that physical activity benefits adults regardless of age, sex, race/ethnicity, or health status, the cardiopulmonary responsiveness varies greatly. Approximately 40% of people do not achieve a clinically meaningful benefit despite excellent adherence. On the other hand, 30% of people with poor adherence respond better than expected. Based on our previous observation that both common and rare nonsynonymous mitochondrial DNA (mtDNA) variants are associated with physical activity energy expenditure and cardiopulmonary outcomes, we postulated that these variants are likely to identify cardiopulmonary responsiveness to chronic physical activity. These data formed our central hypothesis that mtDNA sequence variation explains a portion of the heterogeneity in cardiopulmonary responsiveness to chronic physical activity. We have a unique opportunity to test our central hypothesis efficiently and cost-effectively by sequencing the entire 16.5kb of mtDNA in stored samples of participants in the Lifestyle Interventions and Independence for Elders Study (The LIFE study). The LIFE study is a definitive Phase 3 multicenter single-masked Randomized Controlled Trial that evaluates a physical activity program vs. a successful aging health education program. The average follow-up duration of the study is approximately 2.7 yrs, and the participants are 1,592 community-dwelling sedentary persons aged 70-89 yrs with stored genetic material. The completed LIFE Pilot study-a cohort of 396 participants randomized to the same interventions for 12 months-will be used to replicate significant associations. Our hypotheses address the effect of common and rare mtDNA variants on responsiveness to the following cardiopulmonary measures that are being collected as part of the trial: 1) walking speed, 2) blood pressure, and 3) pulmonary capacity. We will integrate clinical, behavioral, and genetic data in models to predict the heterogeneity in cardiopulmonary responsiveness to physical activity. By identifying genetic modifiers, this research will provide a starting point to build a personalized medicine framework to better improve cardiovascular health with physical activity. Identifying these genetic factors may also provide novel insights into the molecular pathways that regulate the cardiovascular adaptation to chronic physical activity. This approach could have a large impact in moving the field toward the NIH's goals of personalizing behavioral interventions for a rapidly aging America.

描述（由申请人提供）：随着老年人的预期寿命持续增加，心血管疾病的流行将上升，年龄较高的人> 75岁，代表了美国人口中增长最快的人群。身体健康不足是主要由久坐的生活方式引起的心肺功能不良的主要因素。增加体育锻炼仍然是改善心血管健康的重中之重，尤其是在老年人中，患有慢性健康状况的风险最大的老年人。虽然人们普遍认为体育活动使成人受益，而不论年龄，种族/种族或健康状况如何状态，心肺反应性差异很大。尽管有很高的依从性，大约有40％的人没有获得临床意义的好处。另一方面，依从性差的人中有30％的反应比预期的要好。基于我们以前的观察，即常见和稀有的非同义线粒体DNA（mtDNA）变体都与体育活动能量消耗和心肺结果有关，我们假设这些变体很可能鉴定出对慢性身体活动的心肺反应能力。这些数据构成了我们的中心假设，即mtDNA序列变化解释了心肺对慢性体育活动的异质性的一部分。我们有一个独特的机会，可以通过在生活方式干预中存储的参与者样本中对整个16.5kb的mtDNA进行测序，从而有效地测试我们的中心假设，并进行了长者研究的独立性（Life Life研究）。生命研究是一项确定的3阶段多中心单掩蔽随机对照试验，该试验评估了一项体育锻炼计划与成功的衰老健康教育计划。该研究的平均随访时间约为2.7岁，参与者是1,592个久坐的久坐久坐的久坐的人，年龄在70 - 89年之间，遗传遗传材料。完整的生命试验研究 - A组成的396名参与者的队列随机进行12个月的相同干预措施，将用于复制重要的关联。我们的假设解决了常见和稀有mtDNA变体对以下对心肺措施的反应性的影响，这些措施作为试验的一部分：1）步行速度，2）血压和3）肺能力。我们将在模型中整合临床，行为和遗传数据，以预测心肺对体育活动的异质性。通过识别遗传修饰符，这项研究将为建立个性化医学框架提供一个起点，以更好地改善通过体育锻炼来改善心血管健康。识别这些遗传因素也可能提供对调节心血管适应慢性体育活动的分子途径的新见解。这种方法可能会对迅速衰老的美国的个性化行为干预的个性化行为干预的目标产生巨大影响。