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

项目概要 了解饮酒对骨骼健康的影响很重要，因为酒精会影响骨骼 新陈代谢，超过一半的美国成年人饮用酒精饮料。低至 适度饮酒通常对骨骼有益，而慢性饮酒则对骨骼有益。 酗酒会使人容易骨折。我们研究的长期目标是描绘 介导低/中度和重度饮酒不同骨骼效应的主要机制。 了解酒精对骨代谢的精确影响和作用机制非常重要 因为骨骼健康状况不佳会带来巨大的经济、社会和个人负担。进展情况 了解酒精对骨代谢的作用受到以下因素的阻碍：（1）极其困难 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，以及（4）难以 在动物身上准确地复制人类的饮酒行为。本 R01 申请中提出的研究将 通过使用非人类灵长类动物（猴子）模型克服人类和先前动物研究的局限性 模仿人类全方位饮酒行为的自愿饮酒。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来建立 饮酒模式（不饮酒、轻度/中度、暴饮暴食、大量和非常大量）对骨骼的影响 恒河猴（Macaca mulatta；n=105）和食蟹猴（Macaca fasciculis；n=86）的新陈代谢 性别、年龄和酒精引起的组织和器官系统扰动可能影响骨骼。我们 将通过确定酒精对特定蛋白质（例如肽 激素和细胞因子）和血液中的小分子（例如类固醇激素）效应物。我们的中央 部分基于我们对大鼠、猕猴和人类的初步数据的假设是，血液的变化 来自多种组织/器官的骨活性激素和细胞因子水平对酒精的反应 摄入量协同调节骨细胞数量和活性。为了检验我们的假设，我们提出 以下两个具体目标： 具体目标 1：定义数量和数量之间的相关关系 雄性和雌性猕猴的酒精消耗和骨骼模式。具体目标 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志物之间的关系 雄性和雌性猕猴的骨转换。该项目完成后，我们预计 确定骨骼对酒精的反应程度与血清生化的变化相关 骨转换的标志物，反过来又与特定激素循环水平的变化相关 和细胞因子。我们预期发现的主要积极影响是确定关键的潜在因素 负责酒精对骨代谢的复杂的、依赖于环境的作用。

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.