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

• 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
• 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

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.

项目总结/文摘