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: 6869574
• 负责人: JILL SUTTLES
• 金额: $ 35.38万
• 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 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6869574
• 关键词: biological signal transduction; enzyme activity; enzyme linked immunosorbent assay; experimental allergic encephalomyelitis; fatty acid binding protein; gel mobility shift assay; gene expression; keratinocyte; laboratory mouse; ligands; lipoxygenase; macrophage; multiple sclerosis; peroxisome proliferator activated receptor; prostaglandin endoperoxide synthase; tissue /cell culture; transcription factor

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.

描述（由申请人提供）：脂肪酸结合蛋白（FABP）作为多种疏水配体的细胞内受体，并被认为在脂质转运中发挥作用，使疏水化合物能够递送至负责代谢和细胞内信号传导的酶系统。最近的研究强调了脂肪细胞脂肪酸结合蛋白（aP 2）表达缺陷的基因工程小鼠对肥胖诱导的糖尿病和动脉粥样硬化的保护作用。巨噬细胞表达高水平的aP 2和角质形成细胞脂肪酸结合蛋白（mal-1）。AP 2和mal-1是FABP，其已被证明结合过氧化物酶体增殖物激活受体（PPARs）的几种鉴定的配体，所述PPARs包括环氧合酶和脂氧合酶的代谢物。已证明PPAR家族成员在巨噬细胞的基因表达调控中起重要作用。该提案测试了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。已经设计了区分FABPs在隔离PPAR配体与合成PPAR配体中的作用的实验。将评估PPAR活性，并将在野生型和FABP缺陷型巨噬细胞中分析已知受PPAR调节的转录因子的活性。迄今为止收集的数据表明，FABP作为促炎活性的正调节剂，这表明FABP的缺乏可能在自身免疫性炎性疾病中具有保护作用。这一概念得到了实验性自身免疫性脑脊髓炎（EAE）小鼠多发性硬化模型的初步数据的支持。该模型将用于提供在体内分析FABP在自身免疫炎症反应中的功能的方法，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手段，调节巨噬细胞功能的治疗目的。