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：
10877234
负责人：
Ilhem Messaoudi
金额：
$ 11.67万
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/10877234
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 Categories 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 Macrophage Mediating Metabolic Metabolism Modeling Myelogenous Myeloid Cells Myelopoiesis Natural Immunity Outcome Patients Peripheral Peripheral Blood Mononuclear Cell Phenotype Physiology Population Postoperative Period Predisposition Promoter Regions Reporting Research Respiratory Tract Infections Risk Sampling Self Administration Testing Tissues Virus Diseases alcohol availability alcohol effect antimicrobial cancer type chronic alcohol ingestion comparison control cytokine data integration drinking behavior epigenome experimental study fitness histone modification immune activation improved in vivo in vivo Model insight 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.

项目概要大约 7% 的饮酒者患有慢性大量饮酒 (CHD)，这是与感染易感性增加以及伤口愈合和组织修复受损有关导致术后效果不佳。有证据表明，许多这些缺陷是由源自骨髓细胞，特别是循环单核细胞和组织的过度炎症反应常驻巨噬细胞。这些数据主要来自体外研究，其中来自健康的单核细胞供体或细胞系接受高剂量的乙醇处理。然而，CHD 影响的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，我们对先心病背景下异常炎症反应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模型自愿的乙醇自我管理，准确反映人类生理学并概括复杂的人类饮酒行为。使用这个模型，我们的实验室最近证明了 CHD 会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 LPS 的异常反应刺激。然而，这种重编程和表观遗传机制的功能意义控制它仍然未知。重要的是，因为单核细胞是在恒定条件下寿命较短的循环细胞从骨髓中重新增殖，这些观察结果表明造血生态位受到干扰。造血祖细胞的初步单细胞分析表明分化潜力向与酒精相比，骨髓祖细胞更加成熟。然而，祖细胞中的这一观察结果与它们在血液和组织中的分化状态仍不清楚。在此应用中，我们建议测试假设长期饮酒会重新编程单核细胞的表观遗传景观骨髓中的祖细胞产生循环单核细胞，准备过度炎症反应。我们将首先检查冠心病对循环系统功能重编程的影响单核细胞，进行检测以测试其迁移、吞噬和产生适当代谢的能力回应。接下来我们将通过以下方式检查刺激对单核细胞表观遗传景观的影响：评估染色质可及性和特定组蛋白修饰的丰度。最后，我们将确定 CHD 对骨分化潜能、转录组激活和表观遗传重连的影响骨髓祖细胞并将这些数据与从外周血单核细胞获得的数据整合。该提案的完成将为先天性心脏病对骨髓细胞生成的影响和机制提供新的见解它损害了免疫力和宿主防御，并设计干预措施来减轻这些不利的影响事件并改善免疫结果。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Correlates of SARS-CoV-2 anti-RBD IgG antibody titers among persons experiencing homelessness in Los Angeles.

洛杉矶无家可归者中 SARS-CoV-2 抗 RBD IgG 抗体滴度的相关性。

DOI：
发表时间：
2023
期刊：
影响因子：
0
作者：
Nyamathi, Adeline;Shin, Sanghyuk S;Doratt, Brianna M;Jones;Salem, Benissa;Gelberg, Lillian;Lee, Darlene;Garfin, Dana;Yadav, Kartik;Chang, Alicia H;White, Kathryn;Arce, Nicholas;Messaoudi, Ilhem
通讯作者：
Messaoudi, Ilhem

Transcriptional and Epigenetic Regulation of Monocyte and Macrophage Dysfunction by Chronic Alcohol Consumption.

慢性饮酒对单核细胞和巨噬细胞功能障碍的转录和表观遗传调节。