Fatty acid binding proteins in macrophage function

脂肪酸结合蛋白，FABP，已被确定为代谢和蛋白质的中枢调节因子。 炎症途径。FABP作为多种疏水性物质的胞内受体 化合物，使它们能够在细胞质隔间内扩散。我们已经证明了 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，部分是通过调节过氧化物酶的活性 增殖物激活受体(PPAR())。FABP缺陷的巨噬细胞和树突状细胞(DC) 小鼠在促炎细胞因子的表达上存在缺陷，并且在 在抗原呈递过程中促进促炎性T细胞反应。FABP缺陷小鼠 可预防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调节代谢和代谢之间的分子开关。 巨噬细胞和树突状细胞中的炎症通路，因此调节先天和 适应性免疫反应。我们将继续对这些蛋白质的研究，通过追求 具体目标如下：具体目标1确定FABP的分子机制(S) 影响巨噬细胞和DC的炎性细胞因子基因表达。我们发现FABP缺乏 伴随着AMP激活的蛋白激酶(AMPK)活性的升高 AMPK是巨噬细胞炎症功能的负性调节因子。我们将进行一些实验 确定FABP、AMPK和PPAR()之间的联系，检验FABP的假设 能量储备的调节调节AMPK活性，而AMPK活性反过来调节炎症活动。 具体目标2是进一步阐明FABP缺乏对自身免疫性疾病的影响 EAE作为一个模型。这一目标将包括对T细胞启动的具体贡献的评估， 以及组织环境，针对FABP缺陷小鼠表现出的对EAE的保护。 具体目标3是检验FABPs的表达与膳食脂肪摄入量与 加重了炎症性疾病。我们将评估脂肪摄入对FABP表达的影响。 白细胞数量及饮食诱导FABP表达与炎症的关系 响应性。FABP被认为是许多疾病的潜在治疗靶点。这 该提案旨在更全面地了解这些蛋白质是如何调节免疫的 和炎症反应。

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 FABPdeficient 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 FABPdeficiency 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. 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 population and the association of diet-induced FABP expression with inflammatory responsiveness. FABPs are considered potential therapeutic targets for a number of diseases. This proposal is designed to gain a more complete understanding of how these proteins regulate immune and inflammatory responses.