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

成纤维细胞生长因子（Fibroblast Growth Factor， FGF）具有促进成纤维细胞生长的作用。在没有细胞增殖发生的大脑中发现了大量的GFG，这表明FGF在大脑中的生理意义。近年来的一系列证据表明，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至关重要的神经营养因子。因此，FGF是预防或治疗随着年龄增长而丧失学习记忆能力的良好候选药物。然而，FGF有潜在的癌症风险，因为它在细胞增殖中的作用。因此，开发在脑中选择性有效且缺乏有丝分裂活性的改性FGF具有重要意义。作为开发这种新型FGF的第一步，我们已经使用蛋白质工程技术研究了FGF的哪个区域对大脑活动至关重要。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）及碱性成纤维细胞生长因子修饰的相关肽对食物和摄取量的影响。第三脑室输注aFGF和bFGF可显著抑制食物摄入。aFGF对摄食的抑制作用是bFGF的1.5倍。输注aFGF的羧基端片段aFGF-(114-140)确实影响食物摄入，而aFGF的氨基端片段aFGF-(1-15)则有明显的抑制作用。其他氨基末端片段aFGF-(1-20)和aFGF-(1-29)不影响食物摄入。然而，用丙氨酸取代16位半胱氨酸残基的aFGF-(1-29) [Ala16]显著抑制了食物摄入。结果提示，aFGF、bFGF及aFGF的某些氨基末端肽参与了摄食的中枢调控。

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.