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: 8064014
• 负责人: JILL SUTTLES
• 金额: $ 36.88万
• 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/8064014
• 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(申请人提供)：脂肪酸结合蛋白，FABP，已被确定为代谢和炎症途径的中心调节者。FABP作为各种疏水化合物的细胞内受体，使它们能够在细胞质内扩散。我们发现脂肪细胞FABP(A-FABP)和上皮性FABP(E-FABP)调节巨噬细胞胆固醇转运和炎症功能，部分是通过调节PPAR-？的活性来实现的。FABP基因缺陷小鼠的巨噬细胞和树突状细胞(DC)缺乏致炎细胞因子的表达，在抗原呈递过程中不能有效地促进致炎T细胞反应。FABP基因缺陷的小鼠可免受实验性自身免疫性脑脊髓炎(EAE)的发展。总体而言，我们的研究结果表明，FABP调节巨噬细胞和DC中代谢和炎症途径之间的分子开关，从而调节先天和获得性免疫反应。我们将继续我们对这些蛋白的研究，以追求以下特定的目标：特定的目标1是确定FABP影响巨噬细胞和DC炎症细胞因子基因表达的分子机制(S)。我们发现FABP缺乏伴随着AMP激活的蛋白激酶(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FABP、AMPK和PPAR-？之间的联系。测试FABP对能量储备的调节调节AMPK活性，进而调节炎症活动的假设。具体目的2是以EAE为模型，进一步阐明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缺陷小鼠所表现出的对EAE的保护的具体贡献。为此，我们还将使用EAE模型测试FABP抑制剂作为抗炎疗法的体内疗效。具体目标3是验证FABP的表达与饮食脂肪摄入量与加剧的炎症性疾病之间存在联系的假设。我们将评估脂肪摄入对白细胞群体中FABP表达的影响，以及饮食诱导的FABP表达与炎症反应的关系。这些研究的完成将提供对FABP如何调节免疫和炎症反应的更全面的了解。 公共卫生相关性：脂肪酸结合蛋白(FABP)已被证明在肥胖和2型糖尿病中发挥作用。这一建议是基于研究表明，FABP还强烈促进炎症和促进自身免疫性炎症性疾病。该项目的目标是确定FABP调节白细胞炎症功能的机制，并检验FABP是治疗炎症性疾病的有效靶点的假设。鉴于最近发现了FABP功能的小分子抑制剂，该项目与人类健康直接相关。