Application of plasma lipidomics to identify novel biomarkers of muscle and hepatic adiposity in population-based cohorts of older Black Caribbeans, Black Americans, and White Americans

应用血浆脂质组学在老年加勒比黑人、美国黑人和美国白人群体中鉴定肌肉和肝脏肥胖的新型生物标志物

• 批准号: 10525296
• 负责人: Megan Michelle Marron
• 金额: $ 12.59万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525296
• 关键词: Abdomen; Activities of Daily Living; Address; Admixture; African; African Caribbean; African ancestry; Age; Aging; American; Behavior; Behavioral; Biochemical; Biochemistry; Biological; Biology; Biomechanics; Black American; Black race; Body Composition; Carbohydrates; Cell physiology; Chronic; Coronary Artery Risk Development in Young Adults Study; Data; Elderly; Energy Metabolism; Environment; Ethnic Origin; European; Fatty Acids; Fatty acid glycerol esters; Funding; Gender; Glucose; Goals; Health; Hepatic; High Prevalence; Homeostasis; Impairment; Individual; Infiltration; Inflammation; Insulin; Insulin Resistance; Intervention; Isotopes; K-Series Research Career Programs; Knowledge; Laboratories; Lead; Leadership; Left; Lipids; Liver; Measures; Mentorship; Metabolic; Metabolic Pathway; Methods; Muscle; National Institute on Aging; Obesity; Organ; Outcome; Participant; Pathogenicity; Pathway interactions; Physical Function; Physiological Processes; Plasma; Population; Principal Investigator; Process; Proteins; Protocols documentation; Race; Research; Research Personnel; Scanning; Secure; Skeletal Muscle; Specificity; Subgroup; Techniques; Technology; Time; Tobago; Training; Triglycerides; Walking; X-Ray Computed Tomography; bean; caucasian American; cohort; design; disability; epidemiology study; geographic difference; health disparity; lipid metabolism; lipidomics; metabolomics; mortality; multidisciplinary; muscle form; novel; novel marker; physically handicapped; population based; preservation; programs; public health relevance; racial and ethnic; racial difference; racial health disparity; research study; saturated fat; skills; uptake

ABSTRACT: Physical disability is common in U.S. older adults, with a higher prevalence in Black vs. White Americans. Physical functioning declines with aging due to biomechanical and biochemical effects. Skeletal muscle and the liver are highly active metabolic organs contributing to biochemical effects involved in multiple physiologic processes. However, with aging, excess fat accumulates ectopically in and around muscle and the liver, impairing normal functioning and causing negative metabolic consequences. In fact, skeletal muscle and the liver share common pathophysiological mechanisms, e.g., insulin resistance and chronic inflammation, that predict physical disability. Individuals of African ancestry have more muscle adiposity, but paradoxically, less liver adiposity than White Americans. A better understanding of the underlying biology of muscle and liver adi- posity in Black vs. White older adults could potentially explain health disparities. Lipidomics is a promising method to better understand metabolic mechanisms underlying muscle and liver adiposity since it directly measures lipids left behind from cellular processes that have shown to have extensive biological relevance. The Principal Investigator, Dr. Marron, previously found several triglycerides were higher and several were lower in older adults with high vs. low walking ability, where the direction in associations directly depended on degree of fatty acid saturation. These findings led to this project, to investigate lipid pathways associated with muscle and liver adiposity, since ectopic fat depots are likely major drivers of functional capacity with aging and both muscle and liver share common pathophysiologic processes that predict disability. Thus, Dr. Marron pro- poses to apply lipidomics to measure >1000 plasma lipids and use existing computed tomography of skeletal muscle and the liver in a subset ages 50+ from the Tobago Study, a Black Caribbean cohort and the Coronary Artery Risk Development in Young Adults (CARDIA) study, a Black and White American cohort. This proposal will: 1) characterize, for the first time, differences in muscle and liver composition in Black Caribbeans, Black Americans, and White Americans; 2) compare associations between lipids and muscle and liver adiposity in Black Caribbeans, Black Americans, and White Americans and assess if differences are driven by ancestry admixture or environment/behavior; and 3) develop and validate a metabolite composite score indicative of muscle and liver health. The career development award will provide protected time for Dr. Marron to cultivate her emerging research program and initiate a path towards independence. The proposal has been designed to 1) gain didactic training in biochemistry, lipid metabolism, and body composition by race/ethnicity; 2) leverage cutting-edge techniques, i.e., untargeted lipidomics with a novel isotope dilution approach and computed to- mography, to expand existing knowledge of underlying pathogenic mechanisms of muscle and liver adiposity; and 3) enhance mentorship and grantsmanship to obtain funding to reach a long-term goal of elucidating novel intervention targets to preserve muscle and liver health and physical functioning with aging.

摘要：身体残疾在美国老年人中很常见，黑人的患病率高于白人 美国人。由于生物力学和生物化学的影响，身体机能随着年龄的增长而下降。骨骼 肌肉和肝脏是高度活跃的代谢器官，参与参与多种生物化学效应 生理过程。然而，随着年龄的增长，多余的脂肪在肌肉和肌肉周围异位积累， 肝脏，损害正常功能，造成负面新陈代谢后果。事实上，骨骼肌和 肝脏有共同的病理生理机制，如胰岛素抵抗和慢性炎症， 预测身体残疾。非洲血统的人肌肉肥胖症更多，但矛盾的是，更少 肝脏肥胖症比美国白人更严重。对肌肉和肝脏的潜在生物学有更好的理解 黑人和白人老年人的姿势可以潜在地解释健康差异。脂质组学是一种很有前途的 方法更好地了解肌肉和肝脏肥胖症的代谢机制 测量细胞过程中遗留下来的已被证明具有广泛生物学相关性的脂质。 首席调查员马龙博士此前发现，有几种甘油三酯含量较高，有几种 行走能力高的老年人与行走能力低的老年人的比例较低，其中联想的方向直接取决于 脂肪酸饱和度。这些发现导致了这个项目，调查与 肌肉和肝脏肥胖，因为异位脂肪库可能是随着年龄和年龄的增长而产生功能能力的主要驱动因素 肌肉和肝脏都有共同的预测残疾的病理生理过程。因此，马龙·普罗博士- 建议应用脂质组学测量&gt；1000血脂并使用现有的骨骼计算机断层扫描 来自多巴哥研究、加勒比黑人队列和冠状动脉的50岁以上人群的肌肉和肝脏 美国黑人和白人队列中的青年动脉风险发展(CARDIA)研究。这项建议 威尔：1)首次描述了黑加勒比、黑加勒比和黑加勒比在肌肉和肝脏组成上的差异 美国人和美国白人；2)比较脂肪、肌肉和肝脏肥胖之间的关系 加勒比黑人、美国黑人和美国白人，并评估差异是否由血统驱动 混合物或环境/行为；以及3)开发和验证代谢物综合分数，其指示 肌肉和肝脏健康。职业发展奖将为马伦博士提供受保护的时间来培养 她正在兴起的研究计划，并开启了一条独立的道路。这项提议旨在 1)根据种族/民族接受生物化学、脂类代谢和身体组成方面的教学培训；2)利用 尖端技术，即使用新的同位素稀释方法的非靶向脂质组学，并计算到- 影像学，以扩大肌肉和肝脏肥胖症潜在发病机制的现有知识； 以及3)加强指导和恩赐精神，以获得资金，以实现阐释小说的长期目标 干预目标是随着年龄的增长保持肌肉和肝脏的健康以及身体功能。