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:
    8265830
  • 负责人:
  • 金额:
    $ 13.29万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-03-01 至 2013-08-31
  • 项目状态:
    已结题

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):酗酒会促进骨质疏松症的发生。据估计,酗酒者中骨质疏松症的患病率为 28-52%,而所有美国成年人的骨质疏松症患病率约为 10%。酗酒还会抑制先天性和后天性免疫功能,导致感染发生率升高,发病率和死亡率增加。这些看似无关的酗酒后果,通过酒精对破骨细胞和骨髓树突细胞 (mDC) 起源的细胞(破骨细胞树突细胞 (ODC) 祖细胞)的影响而错综复杂地联系在一起。由于其在骨骼维护和免疫细胞生成中的作用,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 通路是分别参与 ODC 分化为破骨细胞和 mDC 的两个主要信号系统。这两种信号传导途径的整合通过 NOTCH 信号传导发生。 NOTCH 激活通过抑制 RANK 转录来抑制破骨细胞生成,同时促进 FZD(Wnt 受体)基因表达,增强树突生成。长期饮酒会抑制恒河猴骨髓细胞中的 NOTCH 活性。此外,长期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传导途径之间相互作用的信息很少,并且酒精对这些信号传导和表观遗传机制的影响仍有待研究。我们的假设是,长期饮酒会失调控制 ODC 祖细胞谱系分化平衡的关键信号机制,从而导致破骨细胞生成增强和树突生成受损。旨在解决三个具体目标的实验将检验长期饮酒的假设:(1)通过上调 RANK 信号传导促进破骨细胞生成; (2) 通过抑制 FZD/2-catenin 信号通路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,进一步破坏 ODC 祖细胞分化的平衡。 K99期间将掌握基因组甲基化技术,以及慢病毒载体生产和相关方案。这些技术将用于在 R00 期间完成拟议的研究。资助提案的撰写和指导职责将补充 R00 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许多尖端技术。这项研究还将确定开发治疗干预措施的关键目标,以治疗酗酒者的骨免疫功能障碍。

项目成果

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Robert Wade Siggins其他文献

Robert Wade Siggins的其他文献

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{{ truncateString('Robert Wade Siggins', 18)}}的其他基金

Alcohol-induced Osteoimmunopathies: A Unifying Explanatory Mechanism
酒精引起的骨免疫病:统一的解释机制
  • 批准号:
    8723000
  • 财政年份:
    2013
  • 资助金额:
    $ 13.29万
  • 项目类别:
Alcohol-induced Osteoimmunopathies: A Unifying Explanatory Mechanism
酒精引起的骨免疫病:统一的解释机制
  • 批准号:
    8706302
  • 财政年份:
    2013
  • 资助金额:
    $ 13.29万
  • 项目类别:
Alcohol-induced Osteoimmunopathies: A Unifying Explanatory Mechanism
酒精引起的骨免疫病:统一的解释机制
  • 批准号:
    8517270
  • 财政年份:
    2012
  • 资助金额:
    $ 13.29万
  • 项目类别:
Alcohol-induced Osteoimmunopathies: A Unifying Explanatory Mechanism
酒精引起的骨免疫病:统一的解释机制
  • 批准号:
    8090149
  • 财政年份:
    2011
  • 资助金额:
    $ 13.29万
  • 项目类别:

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