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

成纤维细胞生长因子(成纤维细胞生长因子)以其促进成纤维细胞生长的能力来鉴定。在没有细胞增殖的脑组织中发现大量GFG的存在，提示了脑组织中成纤维细胞生长因子的生理意义。最近的一系列证据表明，成纤维细胞生长因子可能是一种参与学习和记忆的神经物质，也是一种神经营养因子，对神经细胞的生存至关重要。因此，成纤维细胞生长因子是预防或治疗随年龄增长而丧失学习记忆能力的药物的很好候选药物。然而，由于其在细胞增殖中的作用，成纤维细胞生长因子具有潜在的癌症风险。因此，研制一种在脑内选择性有效、缺乏丝裂原活性的改良型成纤维细胞生长因子是非常重要的。作为开发这种改良型成纤维细胞生长因子的第一步，我们利用蛋白质工程技术研究了成纤维细胞生长因子的哪个区域是大脑活动所必需的。研究了酸性成纤维细胞生长因子、碱性成纤维细胞生长因子及其修饰的相关多肽对饮食和摄入量的影响。在第三脑通气孔内注入aFGFs和bFGFs显著抑制摄食量。AFGF抑制摄食的效力是bFGF的1.5倍。输注aFGF的羧基末端片段aFGF-(114-140)不影响摄食量，而氨基末端的aFGF-(1-15)则显著抑制摄食量。其他氨基末端片段aFGF1-20和aFGF1-29不影响摄食量。然而，用丙氨酸取代16位半胱氨酸残基的[Ala16]aFGF-(1-29)显著抑制了摄食量。结果提示，aFGF3、bFGF3及其部分氨基末端多肽参与食物摄入量的中枢调节。

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.