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

开发作用于中枢神经系统的修饰成纤维细胞生长因子。

基本信息

批准号：
03454135
负责人：
ISOBE Masaharu
金额：
$ 4.03万
依托单位：
Toyama Medical and Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1993
项目状态：
已结题

项目摘要

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.

成纤维细胞生长因子（FGF）因其促进成纤维细胞生长的能力而被鉴定。在未发生细胞增殖的大脑中发现大量 GFG 的存在，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和记忆的神经物质，也是一种对神经细胞生存至关重要的神经营养因子。因此，FGF是预防或治疗随衰老而丧失的学习和记忆能力的良好候选药物。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，开发在大脑中选择性有效且缺乏促有丝分裂活性的修饰的FGF非常重要。作为开发这种改良 FGF 的第一步，我们利用蛋白质工程技术研究了 FGF 的哪个区域对于大脑活动至关重要。研究了酸性成纤维细胞生长因子（aFGF）、碱性 FGF（bFGF）和 aFGF 修饰的相关肽对食物和摄入量的影响。将aFGF和bFGF输注至第三脑室可显着抑制食物摄入。 aFGF抑制食物摄入的效力是bFGF的1.5倍。输注 aFGF 的羧基端片段 aFGF-(114-140) 确实会影响食物摄入，而 aFGF 的氨基端片段 aFGF-(1-15) 具有显着的抑制作用。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16位半胱氨酸残基被丙氨酸取代的[Ala16]aFGF-(1-29)显着抑制食物摄入。结果提示aFGF、bFGF以及aFGF的一些氨基端肽参与食物摄入的中枢调节。