Ethanol modulate central and peripheral immune responses via HMGB1, IL-1Beta, and other Immune Signaling Molecules

乙醇通过 HMGB1、IL-1Beta 和其他免疫信号分子调节中枢和外周免疫反应

基本信息

批准号：
10004214
负责人：
Leon Garland Coleman
金额：
$ 13.3万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-08 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004214
关键词：
Accounting Acute Affect Agonist Alcohol abuse Alcohol consumption Alcoholic Hepatitis Alcoholic Liver Diseases Alcoholism Alcohols Autophagocytosis Basic Science Biological Assay Body Surface Brain Burn injury Cell Communication Cell Culture System Cells Cessation of life Chronic Clinical Clinical Research Co-Immunoprecipitations Companions Critical Illness Data Development Disease Doctor of Philosophy Dose Ensure Enzymes Ethanol FRAP1 gene Flow Cytometry Foundations Glycyrrhizic Acid Goals HMGB1 gene Hour Human Immune Immune System Diseases Immune response Immune signaling Immune system In Vitro Inflammation Inflammatory Inflammatory Response Inflammatory Response Pathway Injections Innate Immune Response Innate Immune System Interleukin-1 Interleukin-1 beta Intestinal permeability Kineret Label Laboratories Lead Learning Link Lipids Liver Lung Mass Spectrum Analysis Measures Mediating Mentors Mentorship Microglia Modeling Mus Natural Immunity Neuroglia Neurons Organ Outcome PTEN gene Pathology Pathway interactions Patients Peripheral Pharmacotherapy Plasma Pneumonia Poly I-C Proteins Recording of previous events Recovery Research Research Personnel Role Secondary to Sepsis Severity of illness Signal Pathway Signal Transduction Signaling Molecule Sirolimus Slice Spleen Stomach TLR3 gene TLR4 gene Techniques Testing Time Tissues Viral Western Blotting Work alcohol effect alcohol exposure alcohol use disorder career career development cell type cytokine experimental study fluorescence imaging immune activation immunocytochemistry in vivo inhibitor/antagonist laboratory experience mortality neuroinflammation novel novel therapeutics preventable death problem drinker protective effect research and development response translational scientist uptake vesicular release wortmannin

项目摘要

Project Summary/Abstract Alcohol use disorders are third leading cause of preventable death, accounting for approximately 90,000 preventable deaths each year (Danaei et al 2009). Nearly 50% deaths are secondary to diseases that are associated with inflammation and aberrant immune activation such as sepsis and alcoholic liver disease (Mokdad et al 2000). Recent discoveries find that alcohol activates the innate immune system in both the CNS and periphery. Thus, understanding the effects of alcohol on the immune system is critical to form a foundation of discovery leading to the understanding of both the pathology of alcoholism and numerous alcohol-associated diseases. We have found recently that alcohol activates the innate immune system through the ‘master regulator’ of innate immunity, HMGB1. In this proposal we aim to investigate the effects of alcohol on central and peripheral immune activation through HMGB1 and its companion cytokine IL-. Using in vitro cell culture systems (Aim 1), in vivo experiments (Aim 2-3) and assessments in human alcoholics, burn patients and alcoholic hepatitis patients (Aim 4), we hope to gain an understanding of the immune effects of alcohol throughout the body. I will gain new laboratory experience with real time-PCR, enzyme-linked immunosorbant assays, co-immunoprecipitation, western blotting, intracerebral AAV5 viral injections, mass spectrometry, immunocytochemistry, and live fluorescent imaging. We also investigate a novel mechanism of cell-cell communication in this pathology, alcohol-induced release of pro-inflammatory microparticles. Further, we investigate the role of the PTEN/PI3K/Akt/mTOR pathway in the immune effects of alcohol, and study inhibitors of this pathway which may be novel therapeutic options. Our preliminary data strongly suggest that alcohol causes central and peripheral HMGB1 and IL-1 release in microparticles through a PTEN/PI3K/Akt/mTOR linked mechanism. This project also incorporates substantial career development with career and research mentoring from top tier researchers and clinicians, the learning of new experimental techniques, and course work to enhance clinical/translational expertise. Co-mentors Fulton T. Crews, PhD and Bruce Cairns MD provide a depth of basic science, clinical research, and career development mentorship that will help ensure the successful transition of the candidate to being a top independent translational researcher.

项目概要/摘要酒精使用障碍是可预防死亡的第三大原因，占每年约 90,000 例可预防的死亡（Danaei 等人，2009 年）。死亡是继发于与炎症和异常相关的疾病免疫激活，例如脓毒症和酒精性肝病（Mokdad 等，2000）。最近的发现发现，酒精可以激活人体的先天免疫系统因此，了解酒精对免疫系统的影响。对于形成发现基础以促进理解两者至关重要酒精中毒的病理学我们已经发现了许多与酒精相关的疾病。最近，酒精通过“主调节器”激活先天免疫系统先天免疫，HMGB1 在本提案中，我们旨在研究酒精的影响。通过 HMGB1 及其同伴对中枢和外周免疫激活的影响细胞因子 IL-。使用体外细胞培养系统（目标 1），体内实验（目标 2-3）对人类酗酒者、烧伤患者和酒精性肝炎患者的评估（目标4），我们希望在整个过程中了解酒精对免疫的影响我将获得实时 PCR、酶联技术的新实验室经验。免疫吸附测定、免疫共沉淀、蛋白质印迹、脑内 AAV5 病毒注射、质谱、免疫细胞化学和实时荧光成像。我们还研究了这种病理学中细胞间通讯的新机制，酒精诱导的促炎微粒的释放进一步，我们研究了。 PTEN/PI3K/Akt/mTOR 通路在酒精免疫效应中的作用及研究我们的初步数据表明，该途径的抑制剂可能是新的治疗选择。强烈表明酒精会导致中枢和外周 HMGB1 和 IL-1 释放该项目还通过 PTEN/PI3K/Akt/mTOR 连接机制在微粒中。将实质性的职业发展与职业和研究指导相结合顶级研究人员和忠诚者，学习新的实验技术，以及课程工作旨在提高临床/转化专业知识，共同导师 Fulton T. Crews，博士和布鲁斯·凯恩斯医学博士提供深入的基础科学、临床研究和职业发展指导将有助于确保成功过渡顶级独立转化研究员的候选人。