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

基本信息

批准号：
10531750
负责人：
Ilhem Messaoudi
金额：
$ 6.75万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
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/10531750
关键词：
ATAC-seq Abstinence Address Adverse event Alcohol consumption Alcoholic Liver Diseases Alcohols Animals Area Bacterial Infections Biological Assay Biological Response Modifiers Biology Blood Blood specimen Bone Marrow Cardiovascular Diseases Cell Line Cells Chromatin Chronic Chronic Disease Communicable Diseases Complex Data Defect Development Dose Environment Epigenetic Process Ethanol Etiology Event Failure Female Gene Expression Genetic Transcription Goals Health Heavy Drinking Hematopoietic Hematopoietic stem cells Heterogeneity Homeostasis Host Defense Housing Human Immune Immune Tolerance Immunity Immunocompetence Immunologics Immunology procedure Impaired wound healing In Vitro Individual Infection Inflammation Mediators Inflammatory Inflammatory Response Intercistronic Region Intervention Knowledge Link Macaca Macaca mulatta Mediating Metabolic Metabolism Modeling Myelogenous Myeloid Cells Myelopoiesis Natural Immunity Outcome Patients Peripheral Peripheral Blood Mononuclear Cell Phenotype Physiology Postoperative Period Predisposition Promoter Regions Reporting Research Risk Sampling Self Administration Testing Tissues Viral Respiratory Tract Infection Virus Diseases alcohol availability alcohol effect antimicrobial cancer type chronic alcohol ingestion cytokine drinking behavior epigenome experimental study fitness histone modification immune activation improved in vivo in vivo Model insight macrophage male migration monocyte next generation sequencing nonhuman primate novel pathogen peripheral blood progenitor programs response single cell analysis single-cell RNA sequencing stem cells therapy design tissue repair transcriptome transcriptomics wound healing

项目摘要

PROJECT SUMMARY Approximately ~7% of alcohol-consuming individuals engage in chronic heavy drinking (CHD), which is associated with increased susceptibility to infections as well as impaired wound healing and tissue repair resulting in poor post-operative outcomes. Evidence suggests that many of these defects are mediated by excessive inflammatory responses originating from myeloid cells, notably circulating monocytes and tissue- resident macrophages. These data were primarily generated from in vitro studies where monocytes from healthy donors or cell lines are treated high doses of ethanol. However, the mechanisms underlying the effects of CHD cannot be fully understood by in vitro studies because immune cells carry out their functions in a multicellular environment in which alcohol has widespread effects. Due to a lack of studies utilizing reliable in vivo models, our understanding of the mechanisms underlying aberrant inflammatory responses in the context of CHD remains incomplete. To address these knowledge gaps, we propose to leverage a rhesus macaque model of voluntary ethanol self-administration that accurately mirrors human physiology and recapitulates complex human drinking behavior. Using this model, our lab has recently demonstrated that CHD results in transcriptional and epigenetic rewiring of circulating monocytes and splenic macrophages, resulting in aberrant responses to LPS stimulation. However, the functional implications of this reprogramming and the epigenetic mechanisms controlling it remain unknown. Importantly, because monocytes are short-lived circulating cells under constant repopulation from the bone marrow, these observations suggest perturbations of the hematopoietic niche. Preliminary single-cell analyses of hematopoietic progenitors point to a shift in differentiation potential towards more mature myeloid progenitors with alcohol. However, a link between this observation in progenitor cells and their differentiated states in blood and tissue remains unclear. In this application, we propose to test the hypothesis that chronic alcohol consumption reprograms the epigenetic landscape of monocyte progenitors in the bone marrow giving rise to circulating monocytes poised towards a hyper- inflammatory response. We will first examine the impact of CHD on functional reprogramming of circulating monocytes, implementing assays to test their ability to migrate, phagocytose, and generate proper metabolic responses. We will next examine the effect of stimulation on the monocyte epigenetic landscape through assessment of chromatin accessibility and abundance of specific histone modifications. Finally, we will determine the effect of CHD on the differentiation potential, transcriptome activation, and epigenetic rewiring of bone marrow myeloid progenitors and integrate these data with those obtained from peripheral blood monocytes. Completion of this proposal will provide novel insight into the impact of CHD on myelopoiesis and mechanisms by which it compromised immunity and host defense as well as design interventions to mitigate these adverse events and improve immunological outcomes.

项目摘要大约约7％的饮酒人员从事慢性大量饮酒（CHD），这是与增加感染的敏感性以及伤口愈合受损和组织修复有关导致术后结果不佳。有证据表明，其中许多缺陷是由源自髓样细胞的过度炎症反应，特别是循环单核细胞和组织居民巨噬细胞。这些数据主要是由来自健康的单核细胞的体外研究产生的供体或细胞系被治疗高剂量的乙醇。但是，CHD影响的基础机制体外研究无法完全理解，因为免疫细胞在多细胞中发挥其功能酒精具有广泛影响的环境。由于缺乏利用可靠的体内模型的研究，我们对CHD背景下异常炎症反应的机制的理解仍然不完整。为了解决这些知识差距，我们建议利用恒河猴的猕猴模型自愿乙醇自我给药，可以准确反映人类生理学并概括人类饮酒行为。使用此模型，我们的实验室最近证明了CHD导致转录和循环单核细胞和脾巨噬细胞的表观遗传重新布线，导致对LP的异常反应刺激。但是，此重编程和表观遗传机制的功能含义控制它仍然未知。重要的是，因为单核细胞是恒定的短寿命循环细胞这些观察结果来自骨髓的重生，表明造血生态位的扰动。对造血祖细胞的初步单细胞分析表明，分化潜力转向与酒精相比，更多成熟的髓样祖细胞。但是，祖细胞中这种观察结果与他们在血液和组织中的分化状态尚不清楚。在此应用程序中，我们建议测试慢性饮酒的假设重编程了单核细胞的表观遗传景观骨髓中的祖细胞会产生循环的单核细胞炎症反应。我们将首先检查冠心对循环的功能重编程的影响单核细胞，实施测定以测试其迁移，吞噬细胞的能力并生成适当的代谢回答。接下来，我们将研究刺激对单核细胞表观遗传景观的影响评估染色质的可及性和特定组蛋白修饰的丰度。最后，我们将确定 CHD对骨骼分化潜力，转录组激活和表观遗传学的影响骨髓髓样祖细胞并将这些数据与从外周血单核细胞获得的数据相结合。该提案的完成将提供有关冠心病对骨髓和机制的影响的新颖洞察力通过它损害免疫力和宿主防御以及设计干预措施以减轻这些不利事件并改善免疫学结果。