Impact of chronic ethanol self administration on T cell

长期自我给药乙醇对 T 细胞的影响

基本信息

批准号：
8430375
负责人：
Ilhem Messaoudi
金额：
$ 21.85万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8430375
关键词：
Abstinence Address Aging Alcohol abuse Alcohol consumption Alcohols Animals Autopsy Bacteremia Blood Bronchoalveolar Lavage CD8B1 gene Cause of Death Cell physiology Cellular biology Chronic Communicable Diseases Data Set Defect Development Dose Epithelial Ethanol Eukaryota Frequencies Functional disorder Funding Gene Expression Gene Expression Regulation Grant HIV Heavy Drinking Hepatitis C virus Homeostasis Immune Immune response Immune system Immunity Incidence Infection Infectious Agent Infiltration Inflammation Ingestion Injury to Liver Intervention Laboratories Lead Link Lung Macaca mulatta Measures Mediating Memory Menopause MicroRNAs Modeling Molecular Molecular Profiling Pathology Pathway interactions Pattern Performance Perioperative Peripheral Peripheral Blood Mononuclear Cell Permeability Play Pneumonia Population Populations at Risk Positioning Attribute Post-Transcriptional Regulation Postdoctoral Fellow Predisposition Production Research Personnel Resistance Resistance to infection Reverse Transcription Risk Factors Role Sampling Self Administration Sepsis Severities Small RNA T cell differentiation T cell response T memory cell T-Cell Activation T-Cell Development T-Lymphocyte T-Lymphocyte Subsets Testing Time Training Virus Diseases Water abstracting aged arm chronic alcohol ingestion combat cytokine design drinking immune function immune resistance improved insight mucosal site nonhuman primate novel pathogen peripheral blood problem drinker public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Excessive alcohol consumption inhibits a variety of immunological functions and decreases resistance to several infectious agents, notably HIV and HCV. This increased susceptibility to infection is believed to be mediated by a dysregulation of both the innate and adaptive arms of the immune system. T cells play a critical role in combatting viral infections and several studies have examined the impact of ethanol on T cell responses during infection. However, given that pathogens can interfere with the immune response, it remains critical to understand the impact of ethanol alone on T cell homeostasis. This type of analysis can reveal the mechanistic changes that underlie T cell dysfunction as well as whether it is more pronounced in certain anatomical compartments rendering the alcoholic host more susceptible to specific pathogens. A critical barrier to understanding the relationship between excessive ethanol drinking and T cell dysfunction is the availability of within-subject comprehensive, longitudinal data sets. The rhesus macaque model of ethanol self- administration developed by our Co-Investigator, Dr. Grant, is a robust model wherein animals consume high doses of ethanol for >20 months and can provide these data sets. The studies proposed in this application will address fundamental questions of T cell dysfunction both in the peripheral blood and mucosal sites during chronic ethanol consumption and after repeated periods of abstinence followed by open access to ethanol. More specifically, we will first characterize changes in T cell subsets' frequencies and cytokine production longitudinally in peripheral blood and bronchoalveolar lavage as well as cross-sectionally in the gut. We will then explore molecular mechanisms underlying this dysregulation by identifying ethanol-induced changes in microRNA expression patterns within T cell subsets. MicroRNAs have been shown to modulate immune homeostasis during infection. Moreover, changes in microRNA expression have been linked to liver injury due to chronic excessive drinking. The combination of functional and molecular analyses of the peripheral and mucosal T cell compartment will improve our understanding of ethanol-induced changes in T cell function, thereby aiding in the development of novel interventions to improve immunological performance in this at-risk population.

描述（由申请人提供）：过量的酒精消耗抑制了多种免疫功能，并降低了对几种感染剂，尤其是HIV和HCV的耐药性。人们认为，对感染的敏感性提高是由于免疫系统先天和适应性臂的失调而介导的。 T细胞在对抗病毒感染中起关键作用，几项研究检查了乙醇对感染过程中T细胞反应的影响。但是，鉴于病原体可以干扰免疫反应，因此了解乙醇对T细胞稳态的影响仍然至关重要。这种类型的分析可以揭示T细胞功能障碍构成的机械变化，以及在某些解剖区室中是否更明显，使酒精宿主更容易受到特定病原体的影响。了解过度乙醇饮用和T细胞功能障碍之间关系的关键障碍是受试者内部综合，纵向数据集的可用性。由我们的共同投资者Grant开发的乙醇自我给药的恒河猕猴模型是一种健壮的模型，其中动物消耗了高剂量的乙醇> 20个月，并且可以提供这些数据集。本应用中提出的研究将解决慢性乙醇消耗期间外周血和粘膜部位中T细胞功能障碍的基本问题，以及在戒酒的重复时期，然后开放通往乙醇。更具体地说，我们将首先表征T细胞子集的频率的变化和在外周血和支气管肺泡灌洗以及肠道中横截面的变化。然后，我们将通过鉴定乙醇诱导的T细胞亚群中microRNA表达模式的变化来探索这种失调的分子机制。已显示MicroRNA在感染过程中调节免疫稳态。此外，由于慢性饮酒，microRNA表达的变化与肝损伤有关。周围和粘膜T细胞室的功能和分子分析的结合将提高我们对乙醇诱导的T细胞功能变化的理解，从而有助于发展新的干预措施，以改善这种高危人群中的免疫学性能。