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）通过促进成纤维细胞生长的能力而鉴定出来。在没有细胞增殖的大脑中发现的大量GFG的存在表明FGF在大脑中的生理意义。最近，一系列证据表明，FGF可能是与学习和记忆有关的神经物质，以及神经营养因子，这对于神经细胞的存活很重要。因此，FGF是该药物预防或治疗衰老和治疗记忆力失去能力的良好候选者。但是，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，开发改良的FGF很重要，该FGF在大脑中有效地有效并缺乏有丝分裂活性。作为开发这种模型FGF的第一步，我们研究了FGF的哪个区域对于使用蛋白质工程技术对于大脑的活性至关重要。研究了酸性成纤维细胞生长因子（AFGF），碱性FGF（BFGF）和相关的肽对AFGF修饰的肽对食物和摄入量的影响。将AFGF和BFGF注入第三个脑腹腹式摄入量会显着抑制。 AFGF的效力是BFGF在食物摄入抑制中的效力。 AFGF-（114-140）的羧基末端碎片的输注确实影响了食物的摄入量，而AFGF，AFGF-（1-15）的氨基末端碎片是显着抑制的。其他氨基末端碎片，即AFGF-（1-20）和AFGF-（1-29），也会影响食物摄入量。但是，[ALA16] AFGF-（1-29），其中16位的半胱氨酸残基被丙氨酸取代，可显着抑制食物摄入量。结果表明，AFGF，AFGF的某些氨基末端肽参与食物摄入的中心调节。