权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10252788
负责人：
Sloan Alexandra Lewis
金额：
$ 1.98万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2021-12-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10252788
关键词：
ATAC-seq Abstinence Activities of Daily Living Address Alcohol consumption Alcoholic Liver Diseases Alcohols Animals Bacterial Infections Behavior Binding Biological Assay Biology Blood Bone Marrow Cardiovascular Diseases Cell Line Cells ChIP-seq Chromatin Chronic Communicable Diseases Complex Data Defect Development Dose Epigenetic Process Ethanol Etiology Event Failure Female Gene Expression Genetic Transcription Goals Health Heavy Drinking Hematopoiesis Hematopoietic Hematopoietic stem cells Heterogeneity Human Immune Immunologics Immunology procedure Impaired wound healing Impairment In Vitro Incidence Individual Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Innate Immune System Intercistronic Region Knowledge Laboratories Link Macaca Macaca mulatta Mediating Metabolic Metabolism Modeling Myelogenous Myeloid Cells Myeloid Progenitor Cells Outcome Peripheral Peripheral Blood Mononuclear Cell Phenotype Physiology Postoperative Period Predisposition Promoter Regions Reporting Research Risk Sampling Self Administration Testing Tissues United States Viral Respiratory Tract Infection Virus Diseases alcohol availability alcohol effect alcohol exposure antimicrobial antimicrobial peptide cancer type chronic alcohol ingestion drinking behavior experimental study granulocyte-monocyte progenitors histone modification 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 tissue repair transcription factor transcriptome transcriptomics wound healing

项目摘要

Project Summary: Alcohol consumption is widespread in the United States with ~7% of alcohol-consuming individuals engaging in heavy alcohol use. It is well established that chronic heavy drinking (CHD) 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. However, many of the current studies rely on in vitro exposure of monocytes from healthy donors or cell lines to high doses of ethanol. 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. In order 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 and the epigenetic mechanisms controlling this reprogramming 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 phenotype in progenitor cells and their differentiated states in blood 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 then examine the effect of stimulation on the monocyte epigenetic landscape through assessment of chromatin accessibility and differential binding of histone modifications with alcohol. Finally, we will determine the effect of CHD on the differentiation potential, transcriptome activation, and epigenetic rewiring of bone marrow myeloid progenitors. We will perform functional assays on monocytes derived in vitro from granulocyte/monocyte progenitors and integrate these data with those obtained from peripheral monocytes. Further, scRNA-Seq analysis and epigenetic assessment of the myeloid progenitors will allow us to determine the specific effects of alcohol on the bone marrow compartment and how this leads to hyper-inflammatory, epigenetically reprogrammed peripheral monocytes. Completion of this proposal will expand our knowledge of the immunological effects of alcohol consumption on hematopoiesis.

项目摘要：酒精消费在美国很普遍，约7%的酒精消费者从事酗酒。众所周知，慢性重度饮酒（CHD）与增加易感染以及伤口愈合和组织修复受损，导致术后不良结果。有证据表明，许多这些缺陷是由过度的炎症反应介导的来源于骨髓细胞，特别是循环单核细胞和组织驻留巨噬细胞。但不少目前的研究依赖于来自健康供体或细胞系的单核细胞体外暴露于高剂量的乙醇由于缺乏利用可靠的体内模型的研究， CHD背景下的异常炎症反应仍然不完全。为了解决这些知识差距，我们建议利用恒河猴自愿乙醇自我管理模型，反映了人类的生理机能并概括了人类复杂的饮酒行为。利用这个模型，我们的实验室最近证明CHD导致循环单核细胞的转录和表观遗传重新布线，脾巨噬细胞，导致对LPS刺激的异常反应。然而，以及控制这种重编程的表观遗传机制仍然未知。重要的是因为单核细胞是在来自骨髓的恒定再增殖下的短寿命循环细胞，这些观察表明造血生态位的扰动。造血干细胞的初步单细胞分析祖细胞的分化潜能指向用酒精向更成熟的髓样祖细胞的分化潜能的转变。然而，祖细胞中的这种表型与其在血液中的分化状态之间的联系仍然存在不清楚在这个应用中，我们建议测试慢性酒精消耗重编程的假设，骨髓中单核细胞祖细胞的表观遗传景观引起循环单核细胞正准备进行高度炎症反应我们将首先研究冠心病对循环单核细胞的功能性重编程，实施测定以测试其迁移能力，吞噬并产生适当的代谢反应。然后，我们将研究刺激对通过染色质可及性和组蛋白差异结合评估单核细胞表观遗传景观用酒精改性最后，我们将确定CHD对分化潜力的影响，转录组激活和骨髓髓样祖细胞的表观遗传重新布线。我们将履行职能对体外来源于粒细胞/单核细胞祖细胞的单核细胞进行分析，并将这些数据与从外周单核细胞获得。此外，scRNA-Seq分析和髓系造血干细胞的表观遗传学评估也是一个重要的研究领域。祖细胞将使我们能够确定酒精对骨髓腔室的具体影响，以及如何影响骨髓腔室。这导致高度炎症、表观遗传学重编程的外周单核细胞。完成本这项提案将扩大我们对饮酒对造血的免疫影响的认识。