Program Project: Role of Innate Immunity in Atherosclerosis

计划项目：先天免疫在动脉粥样硬化中的作用

• 批准号: 8289850
• 负责人: Joseph L. Witztum
• 金额: $ 4.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8289850
• 关键词: Adverse effects; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Antibodies; Apoptotic; Area; Arteries; Atherosclerosis; BCL1 Oncogene; Bioinformatics; Biology; Cells; Cellular biology; Characteristics; Chronic; Clinical; Complex; Data; Development; Disease; Disease Progression; Epitopes; Gene Expression; Gene Targeting; Generations; Genetic; Genetic Models; Genomics; Germ Lines; Homeostasis; Immune; Immune response; Immune system; Immunoglobulin M; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Lead; Lesion; Ligands; Lipoproteins; Mediating; Modality; Modeling; Molecular; Mus; Natural Immunity; Nuclear Hormone Receptors; Nuclear Receptors; Pathway interactions; Pattern recognition receptor; Peroxisome Proliferator-Activated Receptors; Plasma; Play; Prevention; Process; Regulation; Role; Seminal; System; Testing; Toll-like receptors; Work; atherogenesis; clinical application; gene function; improved; in vivo; insight; macrophage; novel therapeutic intervention; novel therapeutics; oxidation; oxidized low density lipoprotein; pathogen; programs; receptor binding; reconstitution; response; therapeutic development; translational approach; translational study

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.

描述（由申请人提供）： 我们建议提交新的 PPG 申请，以促进先天免疫系统在动脉粥样硬化形成中的作用的研究。一旦开始，动脉粥样硬化就具有慢性炎症性疾病的所有特征，拟议 PPG 的每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，在病原体识别中发挥关键作用的 TLR 还可以通过介导对修饰脂蛋白和促动脉粥样硬化配体的炎症反应来改变动脉粥样硬化。我们建议结合使用体外和体内方法来了解对相关“病原体”的先天免疫反应的调节及其对炎症和动脉粥样硬化的影响。 有大量证据表明 PPARg 和 PPARd 配体抑制炎症过程，包括 TLR 依赖性机制，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动脉中巨噬细胞和其他细胞的炎症基因表达程序。具体来说，我们将检验以下假设：NCoR/SMRT/SUMOylation 依赖性途径在体外和体内介导 PPARg 的抗炎和抗动脉粥样硬化作用中发挥重要作用，并且 PPARd 通过控制共阻遏物 BCL-6 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。先天免疫的 TLR 能够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、促动脉粥样硬化反应。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共受体、它们相互作用的配体以及负责的分子和细胞机制。先天免疫的第三个焦点是先天 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异性表位。使用所有血浆 IgM 均为 NAb 的重组小鼠，我们将探讨它们在动脉粥样硬化和体内平衡中的作用。我们将探索 TLR 和核受体对 B-1 细胞的调节，并确定发生这种情况的分子途径。总之，我们的研究将加深对免疫调节先天网络的了解，这可能会带来控制炎症和动脉粥样硬化的新治疗选择。