: Complex systems analysis of the impact of alcohol on bone in non-human primates

：酒精对非人类灵长类动物骨骼影响的复杂系统分析

• 批准号: 10165420
• 负责人: URSZULA T IWANIEC
• 金额: $ 32.53万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165420
• 关键词: Adult; Affect; Age; Age of Onset; Alcohol abuse; Alcohol consumption; Alcoholic Beverages; Alcohols; Animal Model; Animals; Biochemical Markers; Blood; Bone Density; Cell Count; Cells; Chronic; Complex; Data; Diet; Economics; Energy Intake; Ethanol; Failure; Female; Fracture; Goals; Grant; Health; Hormones; Human; Individual; Intake; Intervention Studies; Intrinsic factor; Lead; Light; Linear Regressions; Macaca; Macaca fascicularis; Macaca mulatta; Machine Learning; Mediating; Metabolic dysfunction; Modeling; Molecular; Monkeys; National Institute on Alcohol Abuse and Alcoholism; Oregon; Organ; Outcome; Pathology; Pattern; Physiological; Population; Primates; Proteins; Rattus; Research; Research Project Grants; Rhesus; Risk Factors; Serum; Site; Skeleton; Specimen; Strategic Planning; System; Systems Analysis; Testing; Tissues; Transcend; United States; Variant; alcohol effect; alcohol measurement; alcohol research; alcohol response; base; body system; bone; bone cell; bone health; bone mass; bone metabolism; bone turnover; cytokine; density; drinking; drinking behavior; drinking onset; fracture risk; insight; male; multidisciplinary; nonhuman primate; nutrient metabolism; peptide hormone; sex; skeletal; small molecule; social; steroid hormone

PROJECT SUMMARY Understanding the impact of alcohol consumption on bone health is important because alcohol influences bone metabolism and over half of the adult population in the United States drinks alcoholic beverages. Low to moderate levels of alcohol consumption are generally associated with beneficial skeletal effects while chronic alcohol abuse predisposes individuals to bone fractures. The long-term goal of our research is to delineate the primary mechanisms mediating the divergent skeletal effects of low/moderate and heavy alcohol consumption. An appreciation of the precise effects and mechanisms of action of alcohol on bone metabolism is important because of the enormous economic, social and personal burden associated with poor bone health. Progress in understanding the actions of alcohol on bone metabolism are hampered by (1) the extreme difficulty in performing intervention studies in humans, (2) limitations of commonly used animal models, (3) failure to adequately consider alcohol’s effects on tissue and organ systems that impact bone, and (4) difficulty in accurately replicating human drinking behavior in animals. The studies proposed in this R01 application will overcome limitations of human and prior animal studies by using a non-human primate (monkey) model for voluntary alcohol consumption that mimics the full range of human drinking behavior. We will use linear regression models, multivariate linear regression models, machine learning, and systems analysis to establish the impact of pattern of alcohol consumption (none, light/moderate, binge, heavy and very heavy) on bone metabolism in rhesus (Macaca mulatta; n=105) and cynomolgus (Macaca fascicularis; n=86) macaques in the context of sex, age and alcohol-induced perturbations in tissue and organ systems that can influence bone. We will identify the latter perturbations by determining the effect of alcohol on specific protein (e.g., peptide hormones and cytokines) and small molecule (e.g., steroid hormones) effectors in blood. Our central hypothesis, based in part on our preliminary data in rats, macaques and humans, is that changes in the blood levels of bone-active hormones and cytokines, derived from several tissues/organs, in response to alcohol intake act in concert to modulate bone cell number and activity. To test our hypothesis, we propose the following two Specific Aims: Specific Aim 1: Define the correlative relationships between the quantity and pattern of alcohol consumption and bone in male and female macaques. Specific Aim 2: Define the correlative relationships among blood ethanol levels, key bone active hormones and cytokines, and biochemical markers of bone turnover in male and female macaques. At the completion of this project, we expect to have established that the magnitude of skeletal response to alcohol will correlate with changes in serum biochemical markers of bone turnover which, in turn, will correlate with changes in circulating levels of specific hormones and cytokines. The primary positive impact of our anticipated findings is identification of key underlying factors responsible for the complex, context-dependent actions of alcohol on bone metabolism.

项目摘要 了解饮酒对骨骼健康的影响很重要，因为酒精会影响骨骼 代谢和一半以上的美国人口饮用酒精卧室。低到 中等水平的饮酒水平通常与有益的骨骼作用有关，而慢性 酒精滥用使人易于骨折。我们研究的长期目标是描述 介导低/中度和大量饮酒的骨骼影响的主要机制。 对酒精对骨代谢的精确作用和作用机制的欣赏很重要 由于与骨骼健康不良有关的经济，社会和个人燃烧巨大。进步 了解酒精对骨代谢的作用受到（1）极为困难的阻碍 在人类中进行干预研究，（2）常用动物模型的局限性，（3）未能 充分考虑酒精对影响骨骼的组织和器官系统的影响，（4）困难 准确复制动物中的人类饮酒行为。在此R01应用中提出的研究将 通过使用非人类灵长类动物（猴子）模型来克服人类和先前动物研究的局限 自愿饮酒，模仿了人类饮酒行为的全部范围。我们将使用线性 回归模型，多元线性回归模型，机器学习和系统分析以建立 饮酒模式（无，轻/中等，暴饮暴食，沉重且非常重）的影响 恒河猴（Macaca mulatta; n = 105）和cynomolgus（Macaca fascicularis; n = 86）猕猴的代谢 性别，年龄和酒精引起的组织和器官系统的扰动的背景，这些扰动会影响骨骼。我们 将通过确定酒精对特定蛋白的影响（例如Pepperide）来识别后一种扰动 激素和细胞因子）和小分子（例如类固醇激素）在血液中作用。我们的中心 假设部分基于我们在大鼠，猕猴和人类中的初步数据，是血液的变化 骨活性恐怖片和细胞因子的水平，源自几个组织/器官，响应酒精 摄入量协同起作用以调节骨细胞的数量和活性。为了检验我们的假设，我们提出了 以下两个具体目的：特定目标1：定义数量和数量之间的相关关系 男性和女性猕猴的饮酒模式和骨骼的模式。特定目标2：定义相关性 血液乙醇水平，关键骨活性激素和细胞因子以及生化标记之间的关系 男性和女猕猴的骨转换。该项目完成后，我们希望 确定对酒精的骨骼反应的大小将与血清生化的变化相关 骨骼更新的标记，反过来将与特定恐怖的循环水平变化相关 和细胞因子。我们预期的发现的主要积极影响是确定关键基本因素 负责酒精对骨代谢的复杂，上下文依赖的作用。