Fatty Acid Binding Proteins in Macrophage Function

描述（由申请人提供）：脂肪酸结合蛋白（FABPs）作为多种疏水配体的细胞内受体，被认为在脂质转运中发挥作用，使疏水化合物能够传递到负责代谢和细胞内信号传导的酶系统。最近的研究强调了FABPs的重要性，这些研究发现，脂肪细胞脂肪酸结合蛋白（aP2）表达不足的基因工程小鼠对肥胖诱导的糖尿病和动脉粥样硬化都有深刻的保护作用。巨噬细胞表达高水平的aP2和角化细胞脂肪酸结合蛋白（mal-1）。AP2和mal-1是FABPs，已被证明与几种鉴定的过氧化物酶体增殖激活受体（ppar）的配体结合，ppar包括环加氧酶和脂加氧酶的代谢产物。PPAR家族成员已被证明在巨噬细胞基因表达调控中发挥重要作用。本研究验证了FABPs控制PPAR配体的可用性，从而影响巨噬细胞基因表达和功能的假设。实验已经被设计来区分FABPs在PPAR配体的隔离和PPAR配体的合成中的作用。将评估PPAR活性，并分析野生型和fabp缺陷巨噬细胞中已知受PPAR调节的转录因子的活性。迄今收集的数据表明，FABPs是促炎活性的积极调节因子，这表明FABPs的缺失可能对自身免疫性炎症疾病具有保护作用。使用实验性自身免疫性脑脊髓炎（EAE）小鼠多发性硬化症模型的初步数据支持这一概念。该模型将用于提供一种方法来分析体内自身免疫性炎症反应中FABP的功能，其中巨噬细胞促炎活性已被证明是疾病进展的关键。这些研究可能揭示了一种独特的调节巨噬细胞功能的治疗方法。

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 adipocyte fatty acid binding protein (aP2) were found to display profound protection from both obesity-induced diabetes and atherosclerosis. Macrophages express high levels of 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 and lipoxygenase. PPAR family members have been demonstrated to play an important role in the regulation of gene expression in macrophages. This proposal tests the hypothesis that FABPs control the availability of PPAR ligands, thus impacting macrophage gene expression and function. 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. Data collected thus far indicate that FABPs act as positive regulators of pro-inflammatory activity, suggesting that absence of FABPs may be protective in autoimmune inflammatory disease. This concept is supported by preliminary data using the experimental autoimmune encephalomyelitis (EAE) murine model of multiple sclerosis. This model 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.