Mechanisms of Immune Modulation by Abscisic Acid

脱落酸的免疫调节机制

• 批准号: 7680243
• 负责人: Josep Bassaganya-Riera
• 金额: $ 32.34万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7680243
• 关键词: Abscisic Acid; Acids; Adolescent; Agonist; Animals; Antigens; Auxins; Bacterial Antigens; Binding; Biological Assay; Botanicals; Carotenoids; Cells; Communicable Diseases; Complement Factor B; Complex; Conjugated Linoleic Acids; Control Locus; Deltastab; Development; Dinoprostone; Docosahexaenoic Acids; Family suidae; Flowers; Genetic Transcription; Glucose; Goals; Growth; Health; Immune; Immune response; In Vitro; Infection; Inflammation; Inflammatory; Isomerism; Jurkat Cells; Laboratories; Ligands; Lung; Lymphocyte; Mediating; Membrane; Messenger RNA; Modeling; Molecular; Molecular Target; Monocyte Chemoattractant Protein-1; Mus; Nuclear; Nuclear Receptors; Nutrient; Organism; Pathology; Peroxisome Proliferator-Activated Receptors; Plant Growth Regulators; Plants; Pneumonia; Production; Proliferating; Property; Prostaglandins; Regulation; Reporter; Respiratory syncytial virus; Role; Secondary to; Severity of illness; Solutions; Specificity; Staging; T-Cell Proliferation; T-Lymphocyte; Testing; Time; Transcriptional Regulation; Vaccinated; Vaccination; Viral; Virus Diseases; base; biological adaptation to stress; chemokine; cytokine; enantiomer; feeding; gastrointestinal; immune function; immunoregulation; improved; in vivo; influenzavirus; inhibitor/antagonist; lymph nodes; lymphocyte proliferation; mRNA Expression; macrophage; mortality; novel; pathogen; plant growth/development; protein expression; receptor; reproductive; respiratory; response

DESCRIPTION (provided by applicant): Abscisic acid (ABA) is a botanical involved in the regulation of plant growth and a promising immune modulator. ABA activates peroxisome proliferator-activated receptor?? (PPAR ??) in reporter assays and modulates immune function and inflammation in vivo. The long-term goal of this application is to elucidate the cellular and molecular mechanisms by which ABA modulates immune function. Specific Aim 1 will test the hypothesis that ABA modulates lymphocyte proliferation through a PPAR? -dependent mechanism. To test this hypothesis we will: 1) Investigate the ability of ABA's isomers and enantiomers to activate PPAR? in reporter assays in Jurkat cells; 2) Evaluate the specificity of pure ABA enantiomers as PPAR? ligands in binding assays; 3) Use the most effective PPAR? -activating enantiomer for mechanistic studies in vivo to determine whether the expression of PPAR? in immune cells is required for ABA's immunoregulatory actions in influenza virus-vaccinated mice; and 4) Investigate whether the effects of ABA on antigen-specific T cell responses to influenza virus vaccination are secondary to suppression of macrophage-derived PGE2. Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that contributes to the debilitating effects in the host during influenza virus infections. Interestingly, ABA suppresses macrophage MCP-1 mRNA and protein expression. Nuclear factor-?B (NF-?B) is a.central inducer of MCP-1 transcription. Specific Aim 2 will test the hypothesis that ABA down-modulates MCP-1 production through a PPAR?-mediated blockade of NF-?B. Specific aim 2 will dissect the mechanisms of transcriptional regulation of MCP-1 expression by ABA. Specifically, we will: 1) Determine the influence of ABA treatment on the DMA-binding activity of NF-?B in macrophages; 2) Investigate whether ABA represses the expression of NF-?B subunits or induces I?B??expression under inflammatory conditions; 3) Assess the physical interaction of ABA-activated PPAR? and RelA and its role in inhibiting MCP-1 expression in macrophages; and 4) Determine if ABA suppresses the pulmonary inflammatory pathology and MCP-1 expression in the lungs of influenza virus-infected mice by activating PPAR? and inhibiting NF-?B. The mechanistic understanding of the immune modulatory properties of botanicals such as ABA will aid in the development of more efficacious CAM approaches for modulating immune function and ameliorating infectious diseases.

描述（由申请人提供）：脱落酸（ABA）是一种参与植物生长调节的植物药，也是一种有前途的免疫调节剂。 ABA 激活过氧化物酶体增殖物激活受体？ (PPAR??) 在报告基因检测中并调节体内免疫功能和炎症。该应用的长期目标是阐明 ABA 调节免疫功能的细胞和分子机制。具体目标 1 将检验 ABA 通过 PPAR 调节淋巴细胞增殖的假设？依赖机制。为了检验这个假设，我们将： 1) 研究 ABA 的异构体和对映体激活 PPAR 的能力？ Jurkat 细胞的报告基因检测； 2) 评价纯ABA对映体作为PPAR的特异性？结合测定中的配体； 3) 使用最有效的PPAR？ -激活对映体进行体内机制研究以确定PPAR是否表达？免疫细胞中的 ABA 在接种流感病毒的小鼠中发挥免疫调节作用是必需的； 4) 研究 ABA 对流感病毒疫苗接种后抗原特异性 T 细胞反应的影响是否继发于抑制巨噬细胞衍生的 PGE2。单核细胞趋化蛋白-1 (MCP-1) 是一种趋化因子，在流感病毒感染期间会导致宿主衰弱。有趣的是，ABA 抑制巨噬细胞 MCP-1 mRNA 和蛋白质表达。核因子-κB (NF-κB) 是 MCP-1 转录的中央诱导剂。具体目标 2 将检验 ABA 通过 PPAR？介导的 NF-κB 阻断下调 MCP-1 产生的假设。具体目标 2 将剖析 ABA 对 MCP-1 表达的转录调控机制。具体来说，我们将： 1) 确定 ABA 处理对巨噬细胞中 NF-κB DMA 结合活性的影响； 2) 研究炎症条件下ABA是否抑制NF-κB亚基的表达或诱导IκB??的表达； 3) 评估 ABA 激活的 PPAR 的物理相互作用？ RelA及其抑制巨噬细胞MCP-1表达的作用； 4) 确定 ABA 是否通过激活 PPAR 抑制流感病毒感染小鼠肺部的肺部炎症病理和 MCP-1 表达？并抑制 NF-κB。对 ABA 等植物药的免疫调节特性的机制理解将有助于开发更有效的 CAM 方法来调节免疫功能和改善传染病。