: 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: 10415443
• 负责人: URSZULA T IWANIEC
• 金额: $ 7.22万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415443
• 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 SARS-CoV-2, the viral cause of Coronavirus Disease 2019 (COVID-19), is a highly contagious coronavirus, which upon infection results in a non-uniform distribution of clinical response. SARS-CoV-2 infects the lung and other organs, including liver and immune system, with non-lung infections contributing to the etiology of severe COVID-19. Co-morbidity factors associated with poorer health outcomes include male sex, older age, and disease. However, these do not fully explain the distribution of COVID-19 severity, suggesting additional modifying factors. Based on the molecular mechanisms mediating viral infection, excessive alcohol consumption may be an unrecognized factor influencing SARS-CoV-2 infection. Spike proteins on the surface of SARS-CoV-2, and host serine proteases (such as furin and TMPRSS2) and ACE2-expressing receptor sites on target cells are required for SARS-CoV-2 infection. Conversely, ADAM17 (TACE), a major sheddase of ACE2, may lower infection. There is strong circumstantial evidence that alcohol directly increases risk for COVID-19 by altering levels of the enzymes and membrane proteins essential for SARS-CoV-2 infection. Growth hormone/ insulin-like growth factor-1 (GH/IGF-1) and androgen signaling are disturbed by alcohol. GH/IGF-1 signaling is important for regulating levels of furin and ACE2. Androgen signaling is the only known regulator of TMPRSS2 gene transcription, suggesting a plausible mechanism for male sex as a risk factor for severe COVID-19. Additionally, alcohol lowers ADAM17 levels and increases levels of the adipocyte-derived hormone leptin; Adam17 and leptin are important modulators of immune response to viral infection. Based on the literature and preliminary data, we hypothesize alcohol consumption results in undesirable levels of plasma and target cell membrane proteins necessary for or opposing SARS-CoV-2 infection. To test this hypothesis, we propose one Specific Aim: Evaluate the effects of alcohol – in the context of sex, age, and weight – on protein and/or gene expression levels of molecular factors influencing SARS-CoV-2 infection (e.g., ACE2, furin, TMPRSS2 and ADAM17) in archived tissues (plasma, lung, liver, abdominal fat, and bone marrow) from male and female rhesus macaques. The macaques were subjected to voluntary alcohol intake that mimics the full range of human drinking behavior (www.MATRR.com). The proposed research will provide insight into alcohol consumption as a potential life-style factor for increasing risk for infection by SARS-CoV-2 and contributing to poorer health outcomes following infection. The research will also help identify potential interactions between alcohol consumption and intrinsic factors such as sex, age and weight in influencing COVID-19 outcome. The requested supplement is a logical extension of the parent proposal (R01AA026289: Complex Systems Analysis of the Impact of Alcohol on Bone in Non-Human Primates) designed to: (1) determine the contribution of invariant intrinsic factors (e.g., age, sex, species) and variable extrinsic factors (e.g., drinking pattern) on organ effects of alcohol (original focus on bone), and (2) identify the contribution of hormones/cytokines.

项目摘要 SARS-CoV-2是2019年冠状病毒病（COVID-19）的病毒原因，是一种高度传染性的冠状病毒， 其在感染时导致临床反应的不均匀分布。SARS-CoV-2感染肺部， 其他器官，包括肝脏和免疫系统，非肺部感染导致严重 2019冠状病毒病。与较差的健康结果相关的共病因素包括男性、年龄较大和 疾病然而，这些并不能完全解释COVID-19严重程度的分布， 修正因素基于介导病毒感染的分子机制，过量的酒精 消费可能是影响SARS-CoV-2感染的一个未被认识的因素。表面的刺突蛋白 SARS-CoV-2，宿主丝氨酸蛋白酶（如弗林蛋白酶和TMPRSS 2）和ACE 2表达受体位点 是SARS-CoV-2感染所必需的。相反，ADAM 17（TACE），一种主要的脱落酶， ACE 2可能降低感染。有强有力的间接证据表明，酒精直接增加风险， 通过改变SARS-CoV-2感染所必需的酶和膜蛋白的水平来治疗COVID-19。 生长激素/胰岛素样生长因子-1（GH/IGF-1）和雄激素信号传导受到酒精干扰。 GH/IGF-1信号对于调节弗林蛋白酶和ACE 2的水平是重要的。雄激素信号是唯一已知的 TMPRSS 2基因转录的调节因子，这表明男性性别是TMPRSS 2的风险因素， 严重COVID-19。此外，酒精会降低ADAM 17水平，并增加脂肪细胞衍生的 激素瘦素; Adam 17和瘦素是对病毒感染免疫应答的重要调节剂。基于 根据文献和初步数据，我们假设饮酒会导致血浆中不期望的水平 和对抗SARS-CoV-2感染所必需的靶细胞膜蛋白。为了验证这个假设， 我们提出了一个具体的目标：评估酒精的影响-在性别，年龄和体重的背景下- 影响SARS-CoV-2感染的分子因子的蛋白质和/或基因表达水平（例如，ACE 2，弗林蛋白酶， TMPRSS 2和ADAM 17）在来自雄性的存档组织（血浆、肺、肝、腹部脂肪和骨髓）中的表达 和雌性恒河猴。这些猕猴自愿摄入酒精， 人类饮酒行为的范围（www.MATRR.com）。这项拟议中的研究将提供对酒精的深入了解 消费作为一个潜在的生活方式因素，增加感染SARS-CoV-2的风险，并有助于 感染后健康状况较差。这项研究还将有助于确定 饮酒量以及性别、年龄和体重等内在因素对COVID-19结果的影响。的 所要求的补充是母提案（R 01 AA 026289：复杂系统）的逻辑扩展 酒精对非人灵长类动物骨骼影响的分析），旨在：（1）确定 不变的内在因素（例如，年龄、性别、物种）和可变的外在因素（例如，饮酒模式） 酒精对器官的影响（最初关注骨骼），以及（2）确定激素/细胞因子的作用。

项目成果

Effects of Alcohol and Estrogen Receptor Blockade Using ICI 182,780 on Bone in Ovariectomized Rats.

使用 ICI 182,780 阻断酒精和雌激素受体对卵巢切除大鼠骨的影响。

• DOI: 10.1111/acer.14185
• 发表时间: 2019
• 期刊: Alcoholism, clinical and experimental research
• 作者: Wagner,Lindsay;Howe,Kathy;Philbrick,KennethA;Maddalozzo,GianniF;Kuah,AmidaF;Wong,CarmenP;Olson,DawnA;Branscum,AdamJ;Iwaniec,UrszulaT;Turner,RussellT
• 通讯作者: Turner,RussellT