Fatty Acid Binding Proteins in Macrophage Function

描述（由申请人提供）：脂肪酸结合蛋白（FABPs）已被鉴定为代谢和炎症途径的中心调节因子。 FABP作为多种疏水化合物的细胞内受体，使它们能够在细胞质区室内扩散。 我们已经证明脂肪细胞FABP（A-FABP）和上皮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物激活受体（PPAR-？）的活性。 来自FABP缺陷型小鼠的巨噬细胞和树突状细胞（DC）在促炎细胞因子的表达方面有缺陷，并且在抗原呈递期间在促进促炎T细胞应答方面效率低下。 FABP缺陷型小鼠被保护免于发生实验性自身免疫性脑脊髓炎（EAE）。总的来说，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，因此，调节先天性和适应性免疫反应。 我们将继续我们的研究，这些蛋白质通过追求以下具体目标：具体目标1是确定的分子机制（S），其中FABP影响巨噬细胞和DC中的炎症细胞因子基因表达。 我们已经发现FABP缺乏伴随着AMP活化蛋白激酶（AMPK）活性的升高，并且AMPK是巨噬细胞炎症功能的负调节剂。 将进行实验，以确定之间的联系FABP，AMPK，和过氧化物酶体增殖物激活受体-？验证FABP调节能量储存调节AMPK活性，进而调节炎症活性的假设。 具体目标2是使用EAE作为模型进一步描述FABP缺陷对自身免疫性疾病的影响。 这一目标将包括评估T细胞引发和组织环境对FABP缺陷小鼠显示的EAE的保护的具体贡献。 为此，我们还将使用EAE模型测试FABPs抑制剂作为抗炎疗法的体内功效。 具体目标3是检验FABP的表达将膳食脂肪摄入与炎症性疾病恶化联系起来的假设。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。 这些研究的完成将提供对FABPs如何调节免疫和炎症反应的更全面的理解。

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.