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: 10677725
• 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/10677725
• 关键词: Abdomen; Activities of Daily Living; Address; Adipocytes; 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; Diabetes Mellitus; Drug Metabolic Detoxication; Elderly; Energy Metabolism; Environment; Ethnic Origin; Ethnic Population; European ancestry; Fast-Twitch Muscle Fibers; 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; Leadership; Left; Lipids; Lipolysis; 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; Prevalence; Principal Investigator; Process; Proteins; Protocols documentation; Race; Research; Research Personnel; Saturated Fatty Acids; Scanning; Secure; Skeletal Muscle; Specificity; Techniques; Technology; Time; Tobago; Training; Triglycerides; Walking; X-Ray Computed Tomography; bean; caucasian American; cohort; design; disability; epidemiology study; fatty acid oxidation; geographic difference; health disparity; lipid metabolism; lipidomics; metabolomics; mortality; multidisciplinary; muscle aging; muscle form; novel; novel marker; physically handicapped; population based; preservation; programs; public health relevance; racial difference; racial health disparity; 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色 美国人由于生物力学和生物化学效应，身体功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，有助于多种生物化学效应， 生理过程然而，随着年龄的增长，多余的脂肪在肌肉和周围异位积累， 肝脏，损害正常功能并造成负面代谢后果。事实上，骨骼肌和 肝脏具有共同的病理生理机制，例如，胰岛素抵抗和慢性炎症， 预测身体残疾。非洲血统的个体有更多的肌肉肥胖，但矛盾的是， 比白色美国人的肝脏肥胖。更好地了解肌肉和肝脏adi的潜在生物学- 黑人与白色老年人的肥胖可能解释健康差异。脂质组学是一种很有前途的 一种更好地了解肌肉和肝脏肥胖的代谢机制的方法，因为它直接 测量细胞过程中留下的脂质，这些脂质已被证明具有广泛的生物相关性。 主要研究者Marron博士先前发现几种甘油三酯较高， 步行能力高的老年人比步行能力低的老年人低，其中协会的方向直接取决于 脂肪酸饱和度。这些发现导致了这个项目，研究与糖尿病相关的脂质途径。 肌肉和肝脏肥胖，因为异位脂肪库可能是随着年龄增长的功能能力的主要驱动力， 肌肉和肝脏都具有共同的预测残疾的病理生理过程。因此，马龙博士亲- 提出应用脂质组学测量>1000种血浆脂质，并使用现有的骨骼计算机断层扫描 来自托巴哥研究、加勒比黑人队列和冠状动脉粥样硬化性心脏病研究的50岁以上亚组中的肌肉和肝脏 年轻成人动脉风险发展（CARDIA）研究，一项黑人和白色美国队列研究。这项建议 将：1）表征，第一次，肌肉和肝脏组成的差异在黑加勒比，黑 美国人和白色美国人; 2）比较脂肪与肌肉和肝脏肥胖之间的关系， 加勒比黑人、美国黑人和白色美国人，并评估差异是否由血统驱动 混合物或环境/行为;以及3）开发并验证指示以下的代谢物综合评分： 肌肉和肝脏健康。职业发展奖将为马龙博士提供受保护的时间， 她的新兴研究计划，并开始走向独立的道路。该提案旨在 1)通过种族/民族获得生物化学、脂质代谢和身体成分方面的教学培训; 2）杠杆作用 尖端技术，即，非靶向脂质组学与一种新的同位素稀释方法，并计算- mography，以扩大现有的知识，肌肉和肝脏肥胖的潜在致病机制; 3）加强导师制和资助制，以获得资金，从而实现阐明新颖性的长期目标 干预的目标是保持肌肉和肝脏的健康和身体功能随着年龄的增长。