Analysis of Novel Cellular Functions of Fatty Acid Binding Proteins

我们在世界上首次尝试成功地产生了表皮（E）型和脑（B）型脂肪酸结合蛋白（FABPs）的突变小鼠，并在整个项目中对其进行了全面分析。B-FABP突变体在行为学检查中表现出焦虑增强和恐惧记忆增加，而它们仅在新生期降低脑中二十二碳六烯酸（DHA）的含量，而在成年或新生期脑中没有任何组织学变化。B-FABP突变体也表现出减少的前脉冲抑制，其缺陷是精神分裂症的生物标志物。所有的数据表明，B-FABP在精神分裂症的病理学中的一个新的和关键的作用。与野生型相比，E-FABP的突变体在沙门氏菌感染的腹膜炎中表现出较低的死亡率。通过体外分析，与野生型相比，从突变体脾脏中分离的树突状细胞显示出响应于适当刺激的IL-12 p70的产生增强，以及LPS刺激后p38促分裂原活化蛋白激酶和IkBa的磷酸化形式的水平更高。这些结果表明，较低的死亡率在腹膜炎的突变体是由于E-FABP的树突状细胞中的IL-12生产的负调节剂的可能作用。

Mutant mice for epidermal (E)-type and brain (B)-type fatty acid binding proteins (FABPs) were successfully generated as the first attempts in the world by us and they were fully analyzed throughout the project. The mutants for B-FABP exhibited enhanced anxiety and increased fear memory in the behavioral examination, while they decreased the content of docosahezaenoic acid (DHA) in the brain only at neonatal period without any histological changes in the brain at adult or neonate stages. The B-FABP mutants also showed decreased prepulse inhibition whose deficits are a biological marker for schizophrenia. All the data suggest a novel and crucial role of B-FABP in the pathology of schizophrenia. The mutants for E-FABP exhibited a lower mortality rate in the peritonitis by infection of Salmonella as compared with the wild counterpart. By in vitro analysis, dendritic cells isolated from the mutant spleen showed enhanced production of IL-12p70 in response to appropriate stimuli and higher levels of phosphorylated forms of p38 mitogen-activated protein kinase and IkBa after LPS stimulation as compared with the wild. These results suggest that the lower mortality rate in the peritonitis of the mutants was due to the possible role of E-FABP as a negative regulator of IL-12 production in the dendritic cells.