Impact of chronic alcohol consumption on the functional and epigenetic landscapes of monocytes and their progenitors

长期饮酒对单核细胞及其祖细胞功能和表观遗传景观的影响

• 批准号: 10616854
• 负责人: Ilhem Messaoudi
• 金额: $ 12.89万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10616854
• 关键词: Acute Respiratory Distress Syndrome; Address; Alcoholic Liver Diseases; Alcohols; Alveolar Macrophages; Anti-Bacterial Agents; Apoptosis; Bacterial Infections; Blood; Cardiovascular Diseases; Ceramides; Chronic; Communicable Diseases; Defect; Disease; Epigenetic Process; Ethanol; Exhibits; Functional disorder; Health; Heavy Drinking; Host Defense; Immune; Immune response; Immunity; Incidence; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Lead; Life; Link; Lipids; Liver diseases; Lung; Lung diseases; Macaca; Malignant Neoplasms; Mentors; Modeling; Mycoses; Outcome; Oxygen; Parents; Patients; Play; Predisposition; Process; Production; Reporting; Respiratory Disease; Respiratory Tract Infections; Risk; Role; Self Administration; Signal Transduction; Sphingolipids; Syndrome; Technical Expertise; Testing; Viral; Virus Diseases; Work; arm; chronic alcohol ingestion; drinking; lung injury; macrophage; monocyte; nonhuman primate; oxidative damage; progenitor

SUMMARY Chronic heavy drinking (CHD) is associated with multiple adverse health outcomes including increased incidence of liver disease, cardiovascular disease, cancer, and/or infectious disease. Given the increased incidence of viral, bacterial, and/or fungal infections often seen in patients with CHD, this suggests that alcohol can have a significant impact on the host immune response and host defense. Several studies have shown that the most dramatic and consistent changes induced by CHD are evident in the innate immune arm. Using a non-human primate (NHP) model of voluntary ethanol self-administration, we have reported significant defects in monocytes/macrophages. CHD is also associated with increased risk for respiratory infection and disease, notably acute respiratory distress disease syndrome (ARDS). Alveolar macrophages play a critical role in the inflammatory process associated with ARDS. More recently, we have reported that alveolar macrophages from CHD macaques exhibit signs of increased oxidative damage, generate an exaggerated inflammatory response, and dampened anti-bacterial and anti-viral immune responses; thereby providing a link between CHD and increased incidence of ARDS. However, exact mechanisms remain poorly understood. The purpose of this diversity supplement is to support Dr. Jamie Sturgill to test the hypothesis that dysregulation of ceramide levels and signaling in alveolar macrophage with CHD leads to exacerbated inflammatory responses. Previous work by the Sturgill lab has shown that ceramide is a critical sphingolipid in the lung and that alterations of ceramide signaling lead to increased reactive oxygen production, macrophage inflammatory responses, apoptosis, and pulmonary dysfunction. Moreover, ceramide levels are increased in patients with alcoholic liver disease. Thus, ceramide is a logical target to investigate. This supplement is in line with the parent R01 that is investigating mechanisms of aberrant inflammation by circulating monocytes. This supplement will allow Dr. Sturgill to address a critical gap in our knowledge in a focused and mentored project while honing technical skills and gaining expertise in the field of alcohol and immunity in order to facilitate her ability to submit an R01 proposal to further interrogate the effects of CHD on pulmonary disease.

摘要 长期大量饮酒(CHD)与多种不良健康后果有关，包括 肝脏疾病、心血管疾病、癌症和/或传染病的发病率。鉴于增加的 在冠心病患者中常见的病毒、细菌和/或真菌感染的发生率，这表明酒精 可以对宿主的免疫反应和宿主防御产生重大影响。多项研究表明 由CHD引起的最戏剧性和持续的变化在先天免疫臂中很明显。使用 非人灵长类动物(NHP)自愿乙醇自我给药的模型，我们已经报道了重大缺陷 在单核/巨噬细胞中。冠心病还与呼吸道感染和疾病的风险增加有关， 特别是急性呼吸窘迫综合症(ARDS)。肺泡巨噬细胞在肺泡灌洗液中起重要作用 与ARDS相关的炎症过程。最近，我们报道了肺泡巨噬细胞 来自CHD的猕猴表现出氧化损伤增加的迹象，产生夸大的炎症 反应，并抑制抗细菌和抗病毒免疫反应；从而在 冠心病和ARDS发病率的增加。然而，确切的机制仍然知之甚少。目的 这一多样性补充的目的是支持杰米·斯特吉尔博士测试以下假说 冠心病患者肺泡巨噬细胞神经酰胺水平及其信号转导导致炎症加重 回应。斯特吉尔实验室以前的研究表明，神经酰胺是肺中一种关键的鞘磷脂， 神经酰胺信号的改变导致活性氧产生增加，巨噬细胞炎症 反应、细胞凋亡和肺功能障碍。此外，神经酰胺水平在慢性阻塞性肺疾病患者中升高 酒精性肝病。因此，神经酰胺是一个合理的研究目标。本补充资料符合 亲本R01，正在研究循环单核细胞异常炎症的机制。这 补充资料将使斯特吉尔博士能够在一个有重点和有指导的项目中解决我们知识中的关键差距 同时磨练技术技能，获得酒精和免疫领域的专业知识，以方便她 有能力提交R01提案，以进一步询问CHD对肺部疾病的影响。