Analysis of Novel Cellular Functions of Fatty Acid Binding Proteins

我们在世界上首次成功培育出表皮(E)型和脑(B)型脂肪酸结合蛋白(FABP)突变小鼠，并在整个项目中对它们进行了全面的分析。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强，而它们只在新生期降低了脑中二十二碳二烯酸(DHA)的含量，而在成年期和新生期脑组织没有任何组织学变化。B-FABP突变体也显示出脉冲前抑制减少，其缺陷是精神分裂症的生物标志。所有数据表明，B-FABP在精神分裂症的病理中扮演了一个新的和关键的角色。与野生型相比，E-FABP突变体在沙门氏菌感染腹膜炎中的死亡率较低。通过体外分析，从突变的脾中分离的树突状细胞在适当的刺激下产生的IL-12p70增加，并且在脂多糖刺激后p38丝裂原激活的蛋白激酶和IkBA的磷酸化形式水平比野生的高。这些结果提示，突变体的腹膜炎死亡率较低是由于E-FABP可能作为树突状细胞产生IL-12的负调节因子所致。

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.