Development of mcdified fibroblast growth factors which act in central nervcus system.

成纤维细胞生长因子（FGF）是通过其促进成纤维细胞生长的能力而鉴定的。在没有细胞增殖发生的脑中发现的显著量的GFG的存在表明FGF在脑中的生理意义。近年来，一系列研究表明，FGF可能是一种参与学习记忆的神经物质，也是一种对神经细胞存活起重要作用的神经营养因子。因此，FGF是预防或治疗沿着衰老的学习记忆能力丧失的药物的良好候选者。然而，FGF由于其在细胞增殖中的作用而具有潜在的癌症风险。因此，重要的是开发在脑中选择性有效且缺乏促有丝分裂活性的修饰的FGF。作为开发这种修饰的FGF的第一步，我们使用蛋白质工程技术研究了FGF的哪个区域对于大脑中的活性是必不可少的。本文研究了酸性成纤维细胞生长因子（aFGF）、碱性成纤维细胞生长因子（bFGF）及其修饰肽对大鼠摄食量的影响。第三脑室灌注aFGF和bFGF可显著抑制摄食。aFGF的摄食抑制效力是bFGF的1.5倍。输注aFGF的羧基末端片段aFGF-（114-140）确实会影响食物摄入，而aFGF的氨基末端片段aFGF-（1-15）则具有显著的抑制作用。其他氨基末端片段aFGF-（1-20）和aFGF-（1-29）确实影响食物摄入。然而，其中第16位的半胱氨酸残基被丙氨酸取代的[Ala 16]aFGF-（1-29）显著抑制食物摄入。结果提示aFGF、bFGF及其氨基末端肽参与摄食的中枢调节。

Fibroblast Growth Factor (FGF) was identified by its ability to promote the growth of fibroblast. The presence of significant amount of GFG found in the brain where no cell-proliferation occurs, suggests the physiological significance of FGF in the brain. Recently a line of evidences suggest that FGF may be a neural substance involved in learning and memory as well as a neurotrophic factor which is important for survival of neural cells. Thus FGF is a good candidate for the drug to prevent or treat the losing ability of learning and memory along with aging. however FGF has a potential risk of cancers because of its role in cell proliferation. Thus it is important to develop modified FGF which is selectively effective in the brain and lacking the mitogenic activity. As a first step to develop such a modefied FGF, we have investigated which region of FGF is essential for the activity in the brain using protein engineering techniques. The effects of acidic fibroblast growth factor (aFGF), basic FGF(bFGF), and related peptide modified from aFGF, on food and intake were investigated. Infusion of aFGF and bFGF into the third cerebral venticle significantly suppressed food intake. The potency of aFGF was 1.5 that of bFGF in food intake inhibition. Infusion of a carboxyl-terminal fragment of aFGF, aFGF-(114-140), did knot affect food intake, whereas an amino-terminal fragment of aFGF, aFGF-(1-15), was significantly inhibitory. Other amino-terminal fragments, aFGF-(1-20) and aFGF-(1-29), did knot affect food intake. However, [Ala16]aFGF-(1-29) in which the cysteine residue at position 16 was replaced with alanine significantly suppressed food intake. The results suggest that aFGF, bFGF and some amino-terminal peptide of aFGF participate in the central regulation of food intake.