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Alcohol-induced Osteoimmunopathies: A Unifying Explanatory Mechanism

酒精引起的骨免疫病：统一的解释机制

基本信息

批准号：
8517270
负责人：
Robert Wade Siggins
金额：
$ 2.79万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8517270
关键词：
Abbreviations Address Adult Alcohol abuse Alcohols American Antigen-Presenting Cells Applications Grants Bone Diseases Bone Marrow Bone Marrow Cells Cell Count Cell Differentiation process Cells Cellular Structures Chronic Complement Consumption Data Dendritic Cells Development Disease Effector Cell Enhancers Epigenetic Process Equilibrium Ethanol FZD2 gene Functional disorder Gene Expression Genes Genetic Transcription Genome Health Homeostasis Homologous Gene Hypermethylation Immune Immune response Immune system Immunosuppression In Vitro Incidence Infection Investigation Knowledge Laboratory Research Lentivirus Vector Link Macaca mulatta Maintenance Marrow Mediating Medical Mentors Messenger RNA Methylation Modeling Molecular Biology Morbidity - disease rate Mouse Mammary Tumor Virus Mus Myelogenous Nuclear Osteoclasts Osteoporosis Outcome Pathway interactions Patients Phase Plant Roots Population Pre-Clinical Model Prevalence Production Protocols documentation Receptor Gene Research Risk Role Signal Pathway Signal Transduction Signal Transduction Pathway Site Skeletal system Stem cells System Techniques Technology Testing Therapeutic Intervention Tissues Up-Regulation Viral Oncogene Writing alcohol effect bone bone metabolism chronic alcohol ingestion clinically relevant design immune function in vivo mortality novel osteoclastogenesis osteosarcoma precursor cell problem drinker progenitor promoter receptor research study therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Alcohol abuse promotes the development of osteoporosis. The prevalence of osteoporosis in alcohol abusers is estimated to be 28-52% compared to approximately 10% prevalence for all adult Americans. Alcohol abuse also suppresses both innate and acquired immune function leading to a higher incidence of infections with increased morbidity and mortality. These apparently unrelated outcomes of alcohol abuse are intricately linked through the effects of alcohol on the cell that is the origin of both osteoclasts and myeloid dendritic cells (mDCs): the osteoclast-dendritic cell (ODC) progenitor. Because of its role in bone maintenance and immune cell production, the ODC is a linchpin of the skeletal and immune systems. This interdependence makes the osteoimmune system particularly vulnerable to the effects of chronic alcohol consumption on the ODC. RANK/c-FOS and Wnt/Frizzled (FZD)/2-catenin pathways are two major signaling systems involved in ODC differentiation to osteoclasts and mDCs, respectively. Integration of these two signaling pathways occurs through NOTCH signaling. NOTCH activation suppresses osteoclastogenesis through inhibiting RANK transcription while promoting FZD (Wnt receptor) gene expression, enhancing dendropoiesis. Chronic alcohol consumption suppressed NOTCH activity in bone marrow cells of rhesus macaques. Furthermore, chronic alcohol consumption increased RANK expression and decreased FZD receptor gene expression through epigenetic mechanisms (RANK promoter CpG hypomethylation and FZD promoter CpG hypermethylation). Little information is available regarding the interplay among these progenitor cell signaling pathways, and the impact of alcohol on these signaling and epigenetic mechanisms remains to be examined. Our hypothesis is that chronic alcohol consumption dysregulates key signaling mechanisms controlling the balance of ODC progenitor lineage differentiation, which leads to enhanced osteoclastogenesis and impaired dendropoiesis. Experiments designed to address three Specific Aims will test the hypotheses that chronic alcohol consumption: (1) promotes osteoclastogenesis through upregulation of RANK signaling; (2) impairs dendropoiesis by inhibiting the FZD/2-catenin signaling pathway; and (3) alters promoter CpG methylation in RANK and FZD genes, further unbalancing ODC progenitor cell differentiation. Genome methylation techniques, as well as lentiviral vector production and the associated protocols will be mastered during the K99 period. These techniques will be employed to complete the proposed research during the R00 period. Grant proposal writing and mentoring duties will complement laboratory research during the R00 phase. The proposed experimental approach will employ a clinically relevant model of chronic alcohol consumption in rhesus macaques and a number of cutting edge technologies. This investigation will also identify key targets for developing therapeutic interventions to treat osteoimmune dysfunction in alcohol abusers.

描述（由申请人提供）：酒精滥用促进骨质疏松症的发展。酒精滥用者骨质疏松症的患病率估计为28-52%，而所有成年美国人的患病率约为10%。酗酒还抑制先天性和后天免疫功能，导致感染发生率增加，发病率和死亡率增加。酒精滥用的这些明显不相关的结果通过酒精对破骨细胞和髓样树突细胞（mDC）起源细胞的影响错综复杂地联系在一起：破骨细胞-树突细胞（ODC）祖细胞。由于其在骨骼维护和免疫细胞产生中的作用，ODC是骨骼和免疫系统的关键。这种相互依赖性使得骨免疫系统特别容易受到长期饮酒对ODC的影响。RANK/c-FOS和Wnt/Frizzled（FZD）/2-catenin途径分别是参与ODC向破骨细胞和mDC分化的两个主要信号系统。这两种信号通路的整合通过NOTCH信号传导发生。NOTCH激活通过抑制RANK转录抑制破骨细胞生成，同时促进FZD（Wnt受体）基因表达，增强树突状细胞生成。长期饮酒抑制恒河猴骨髓细胞中NOTCH的活性。此外，慢性饮酒通过表观遗传机制（RANK启动子CpG低甲基化和FZD启动子CpG高甲基化）增加RANK表达并降低FZD受体基因表达。关于这些祖细胞信号通路之间的相互作用的信息很少，酒精对这些信号和表观遗传机制的影响仍有待研究。我们的假设是，长期饮酒失调的关键信号机制控制的平衡ODC祖细胞谱系分化，从而导致破骨细胞生成增强和受损的树突状细胞。旨在解决三个特定目的的实验将检验以下假设：慢性饮酒：（1）通过RANK信号传导上调促进破骨细胞生成;（2）通过抑制FZD/2-连环蛋白信号传导途径损害树突状细胞生成;（3）改变RANK和FZD基因中的启动子CpG甲基化，进一步失衡ODC祖细胞分化。基因组甲基化技术，以及慢病毒载体生产和相关的协议将在K99期间掌握。这些技术将用于在R 00期间完成拟议的研究。赠款提案的写作和指导职责将补充在R 00阶段的实验室研究。拟议的实验方法将采用恒河猴慢性饮酒的临床相关模型和一些尖端技术。这项研究还将确定开发治疗干预措施以治疗酗酒者骨免疫功能障碍的关键目标。