Fatty Acid Binding Proteins in Macrophage Function

描述（由申请人提供）：脂肪酸结合蛋白（FABP）作为 各种疏水配体的细胞内受体， 在脂质转运中发挥作用，使得能够递送疏水化合物 负责新陈代谢和细胞内信号传导的酶系统。的 最近的研究强调了FABPs的重要性， 发现aP 2表达缺陷的工程小鼠显示出深刻的 预防肥胖引起的糖尿病和动脉粥样硬化。巨噬 表达高水平的脂肪细胞脂肪酸结合蛋白（aP 2）， 角质形成细胞脂肪酸结合蛋白（maI- 1）。AP 2和mal- 1是FABP， 已经证明其结合几种鉴定的配体， 过氧化物酶体增殖物激活受体（PPARs），包括代谢产物 环氧合酶（考克斯）和脂氧合酶（LOX）。PPAR家族成员 在基因表达的调节中发挥作用， 巨噬细胞使用aP 2和mal- 1缺陷小鼠生成的初步数据 提示这些FABP在巨噬细胞的调节中起基础作用 功能这一提议检验了FABP控制 PPAR配体，从而影响巨噬细胞基因表达。实验已经 设计了区分FABPs在隔离PPAR中的作用 配体与PPAR配体的合成。将评估PPAR活性， 并且已知由PPARS调节的转录因子的活性将 在野生型和FABP缺陷型巨噬细胞中进行分析。的可能性 FABP调节脂肪酸前体对LOX和考克斯的可用性， 通过分析考克斯和LOX代谢物进行评价。有数据表明 降低促炎性细胞因子/趋化因子的表达， 从FABP缺陷小鼠衍生的巨噬细胞，很可能缺乏 aP 2和/或mal- 1将影响炎性细胞因子的发生或进展。 疾病实验性自身免疫性脑脊髓炎（EAE）小鼠模型 多发性硬化症将提供一种分析FABP的方法 在体内，在自身免疫炎症反应中，巨噬细胞 促炎活性已被证明是进展的关键， 疾病这些研究可能揭示了一种调节巨噬细胞的独特方法， 用于治疗目的。

DESCRIPTION (provided by applicant): Fatty acid binding proteins (FABPs) act as intracellular receptors for a variety of hydrophobic ligands and are believed to play a role in lipid transport, enabling delivery of hydrophobic compounds to enzyme systems responsible for metabolism and intracellular signaling. The importance of FABPs has been underscored by recent studies in which genetically engineered mice deficient in expression of aP2 were found to display profound protection from both obesity-induced diabetes and atherosclerosis. Macrophages express high levels of adipocyte fatty acid binding protein (aP2) and keratinocyte fatty acid binding protein (mal- 1). AP2 and mal- 1 are FABPs, which have been demonstrated to bind several identified ligands for the peroxisome proliferator-activated receptors (PPARs), which include metabolites of cyclooxygenase (COX) and lipoxygenase (LOX). PPAR family members have been demonstrated to play a role in the regulation of gene expression in macrophages. Preliminary data generated using aP2 and mal- 1 deficient mice suggest that these FABPs play a basic role in the regulation of macrophage function. This proposal tests the hypothesis FABPs control the availability of PPAR ligands, thus impacting macrophage gene expression. Experiments have been designed which distinguish between a role of FABPs in sequestration of PPAR ligands versus the synthesis of PPAR ligands. PPAR activity will be assessed, and the activity of transcription factors known to be regulated by PPARS will be analyzed in wild type and FABP-deficient macrophages. The possibility that FABPs regulate availability of fatty acid precursors to LOX and COX will be evaluated via analysis of COX and LOX metabolites. Given data demonstrating reduced expression of pro-inflammatory cytokine/chemokine expression by macrophages derived from FABP-deficient mice, it is likely that the absence of aP2 and/or mal- 1 will influence the onset or progression of inflammatory disease. The experimental autoimmune encephalomyelitis (EAE) murine model of multiple sclerosis will be employed to provide a means to analyze FABP function, in vivo, in an autoimmune inflammatory response in which macrophage pro-inflammatory activity has been shown to be key to the progression of disease. These studies may reveal a unique means of modulating macrophage function for therapeutic purposes.