Program Project: Role of Innate Immunity in Atherosclerosis

描述(由申请人提供)： 我们建议提交一份新的PPG申请，以便于研究先天免疫系统在动脉粥样硬化形成中的作用。一旦启动，动脉粥样硬化就具有慢性炎症性疾病的所有特征，拟议的PPG的每一位项目负责人都为认识到免疫机制在调节疾病进展中发挥核心作用做出了重要贡献。体内研究和我们自己的数据表明，TLRs在病原体识别中发挥关键作用，也通过介导对修饰的脂蛋白和致动脉粥样硬化配体的炎症反应来改善动脉粥样硬化。我们建议使用体外和体内相结合的方法来了解对相关病原体的先天免疫反应的调节，以及它们对炎症和动脉粥样硬化的影响。 有广泛的证据表明，PPARg和PPARd配体抑制炎症过程，包括TLR依赖的机制，我们将结合分子、细胞和基因组学方法来了解它们如何控制炎性基因在巨噬细胞和动脉其他细胞中的表达程序。具体地说，我们将检验这样的假设，即NCoR/SMRT/SUMO化依赖的途径在体内外介导PPARg的抗炎和抗动脉粥样硬化作用中发挥重要作用，并且PPARd通过控制共抑制物bcl6和SMRT的游离和核受体结合部分的浓度来调节炎症状态。这些观察结果与动脉粥样硬化形成的相关性将使用各种独特的基因靶向小鼠模型进行测试。天然免疫的TLRs可感知外源性和内源性病原体，并在巨噬细胞和其他细胞中诱导促炎和致动脉粥样硬化反应。使用各种独特的遗传模型，我们将确定与TR2配对促进动脉粥样硬化的辅助受体，它们相互作用的配体，以及相关的分子和细胞机制。对先天免疫的第三个关注将是先天B-1细胞及其分泌的IgM天然抗体(NAB)，这些抗体似乎针对OxLDL和凋亡细胞上发现的氧化特定表位。利用所有血浆IgM都是NAB的重组小鼠，我们将探索它们在动脉粥样硬化和动态平衡中的作用。我们将探索TLRs和核受体对B-1细胞的调节，并确定发生这种调节的分子途径。总之，我们的研究将提高对免疫调节固有网络的理解，这可能导致控制炎症和动脉粥样硬化的新的治疗选择。

DESCRIPTION (provided by applicant): We propose to submit a new PPG application to facilitate study of the role of the innate immune system in atherogenesis. Once initiated, atherosclerosis has all the characteristics of a chronic inflammatory disease and each Project Leader of the proposed PPG has contributed importantly to the recognition that immunological mechanisms play a central role in modulating disease progression. In vivo studies and our own data suggest that TLRs, which play critical roles in pathogen recognition, also modify atherosclerosis by mediating inflammatory responses to modified lipoproteins and proatherogenic ligands. We propose to use a combination of in vitro and in vivo approaches to understand the regulation of innate immune responses to relevant "pathogens", and their impact on inflammation and atherosclerosis. There is extensive evidence that PPARg and PPARd ligands inhibit inflammatory processes, including TLR-dependent mechanisms, and we will use a combination of molecular, cellular and genomics approaches to understand how they control programs of inflammatory gene expression in macrophages and other cells in the artery. Specifically, we will test the hypothesis that NCoR/SMRT/SUMOylation-dependent pathway plays an important role in vitro and in vivo in mediating the anti-inflammatory and anti-atherogenic effects of PPARg and that PPARd regulates the inflammatory state by control of the concentrations of free and nuclear receptor-bound fractions of the co-repressors BCL-6 and SMRT. The relevance of these observations for atherogenesis will be tested using a variety of unique gene targeted murine models. TLRs of innate immunity sense pathogens, both exogenous and endogenous and induce proinflammatory, proatherogenic responses in macrophages and other cells. Using a variety of unique genetic models, we will determine the coreceptors that pair with TR2 to promote atherosclerosis, the ligands with which they interact, and the molecular and cellular mechanisms responsible. A third focus on innate immunity will be on innate B-1 cells and the IgM natural antibodies (NAbs) they secrete, which appear to target oxidation-specific epitopes as found on OxLDL and apoptotic cells. Using reconstituted mice in which all plasma IgM are NAbs, we will explore their role in atherosclerosis and homeostasis. We will explore the regulation of B-1 cells by TLRs and by nuclear receptors and determine the molecular pathways by which this occurs. In summary, our studies will lead to an increased understanding of the innate network of immune regulation, which could lead to novel therapeutic options to control inflammation and atherosclerosis.