Fatty Acid Binding Proteins in Macrophage Function

巨噬细胞功能中的脂肪酸结合蛋白

• 批准号: 8262406
• 负责人: JILL SUTTLES
• 金额: $ 37.08万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8262406
• 关键词: 5' -AMP-activated protein kinase; AMP-activated protein kinase kinase; Adipocytes; Adipose tissue; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation; Autoimmune Diseases; Autoimmune Process; Automobile Driving; Brain; Cells; Chronic; Cytokine Gene; Data; Dendritic Cells; Development; Diet; Dietary Fats; Diffusion; Disease; Environment; Epithelial; Evaluation; Exhibits; Experimental Autoimmune Encephalomyelitis; Fatty acid glycerol esters; Gene Expression; Genes; Glycogen Synthase Kinases; Goals; Health; Human; Hydroxymethylglutaryl-CoA reductase; IL2RA gene; Immune response; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Intake; Interferons; Interleukin-17; Leukocytes; Link; Lipids; Metabolic; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Play; Population; Production; Protein Deficiency; Proteins; Regulation; Research; Role; Spinal Cord; T cell response; T-Lymphocyte; Testing; Tissues; Transcriptional Activation; Wild Type Mouse; Work; base; cholesterol trafficking; cytokine; disorder risk; fatty acid-binding proteins; feeding; in vivo; inhibitor/antagonist; mTOR protein; macrophage; protein expression; protein function; public health relevance; receptor; research study; response; small molecule; transcription factor

DESCRIPTION (provided by applicant): Fatty acid binding proteins, FABPs, have been identified as central regulators of both metabolic and inflammatory pathways. FABPs act as intracellular receptors for a variety of hydrophobic compounds, enabling their diffusion within the cytoplasmic compartment. We have shown that adipocyte FABP (A-FABP) and epithelial FABP (E-FABP) regulate macrophage cholesterol trafficking and inflammatory function, in part via regulation of the activity of the peroxisome proliferator-activated receptor (PPAR-?). Macrophages and dendritic cells (DC) from FABP- deficient mice are defective in expression of proinflammatory cytokines and are inefficient in the promotion of proinflammatory T cells responses during antigen presentation. FABP-deficient mice are protected from development of experimental autoimmune encephalomyelitis (EAE). Overall, the results of our research suggest that FABPs regulate a molecular switch between metabolic and inflammatory pathways in macrophages and DC and, as a consequence, regulate both innate and adaptive immune responses. We will continue our studies of these proteins through the pursuit of the following specific aims: Specific Aim 1 is to identify the molecular mechanism(s) by which FABPs affect inflammatory cytokine gene expression in macrophages and DC. We have found that FABP-deficiency is accompanied by elevated activity of AMP- activated protein kinase (AMPK) and that AMPK is a negative regulator of macrophage inflammatory function. Experiments will be performed to determine the link between FABPs, AMPK, and PPAR-? testing the hypothesis that FABP regulation of energy stores regulates AMPK activity, which in turn modulates inflammatory activity. Specific Aim 2 is to further delineate the impact of FABP-deficiency on autoimmune disease using EAE as a model. This aim will include an evaluation of the specific contributions of T cell priming, and of the tissue environment, towards the protection from EAE displayed by FABP-deficient mice. In this aim we will also test the in vivo efficacy of inhibitors of FABPs as an anti-inflammatory therapy using the EAE model. Specific Aim 3 is to test the hypothesis that the expression of FABPs links dietary fat intake with exacerbated inflammatory disease. We will evaluate the effects of fat intake on FABP expression in leukocyte populations and the association of diet-induced FABP expression with inflammatory responsiveness. The completion of these studies will provide a more comprehensive understanding of how FABPs regulate immune and inflammatory responses. PUBLIC HEALTH RELEVANCE: Fatty acid-binding proteins (FABPs) have been shown to play a role in obesity and Type 2 diabetes. This proposal is based on studies demonstrating that FABPs also strongly promote inflammation and contribute to autoimmune inflammatory disease. The goals of the project are to determine the mechanisms by which FABPs regulate inflammatory function in leukocytes and to test the hypothesis that FABPs constitute an accessible and effective target for treatment of inflammatory disease. Given the recent identification of small molecule inhibitors of FABP function, this project has direct relevance to human health.

描述（由申请人提供）：脂肪酸结合蛋白（FABPs）已被确定为代谢和炎症途径的中枢调节因子。FABPs作为多种疏水化合物的细胞内受体，使其能够在细胞质室内扩散。我们已经证明，脂肪细胞FABP （A-FABP）和上皮细胞FABP （E-FABP）调节巨噬细胞胆固醇运输和炎症功能，部分通过调节过氧化物酶体增殖激活受体（PPAR-?）的活性。来自FABP缺陷小鼠的巨噬细胞和树突状细胞（DC）在促炎细胞因子的表达上存在缺陷，并且在抗原呈递过程中不能促进促炎T细胞反应。fabp缺陷小鼠免受实验性自身免疫性脑脊髓炎（EAE）的发展。总的来说，我们的研究结果表明，FABPs调节巨噬细胞和DC中代谢和炎症途径之间的分子转换，从而调节先天和适应性免疫反应。我们将通过以下具体目标继续研究这些蛋白质：具体目标1是确定FABPs影响巨噬细胞和DC中炎症细胞因子基因表达的分子机制。我们发现fabp缺乏伴随着AMP活化蛋白激酶（AMPK）活性升高，AMPK是巨噬细胞炎症功能的负调节因子。将进行实验以确定FABPs、AMPK和PPAR-？验证了FABP调节能量储存调节AMPK活性的假设，AMPK活性反过来调节炎症活性。特异性目的2是使用EAE作为模型进一步描述fabp缺乏对自身免疫性疾病的影响。这一目标将包括评估T细胞启动和组织环境对fabp缺陷小鼠显示的EAE保护的具体贡献。为此，我们还将使用EAE模型测试FABPs抑制剂作为抗炎治疗的体内疗效。具体目的3是验证FABPs的表达将饮食脂肪摄入与炎症性疾病加剧联系起来的假设。我们将评估脂肪摄入对白细胞群中FABP表达的影响，以及饮食诱导的FABP表达与炎症反应的关系。这些研究的完成将对FABPs如何调节免疫和炎症反应提供更全面的理解。