权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Development of therapies in polyglutamine diseases using hepatocyte growth factor (HGF)

使用肝细胞生长因子 (HGF) 开发多聚谷氨酰胺疾病疗法

基本信息

批准号：
18599002
负责人：
ADACHI Hiroaki
金额：
$ 2.28万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18599002/
关键词：
spinal and bulbar muscular atrophy hepatocyte erowth factor transgenic mouse androgen receptor CAG repeat neurotrophic factor muscle atrophy muscle weakness ドランスジェニックマウスダブルトランスジェニックマウス

项目摘要

Spinal and bulbar muscular atrophy(SBMA) is an inherited motor neuron disease. The molecular basis of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine(polyQ) tract, in the androgen receptor(Alt) gene. We generated transgenic mouse model expressing the full-length human AR containing either 24 or 97 CAG repeats under the control of a cytomegalovirus enhancer and a chicken β-actin promoter(AR-97Q mice). Hepatocyte growth factor(HGF) was initially identified and molecularly cloned as a potent mitogen for mature hepatocytes. Subsequent studies revealed that HGF exerts multiple biological effects, including mitogenic, motogenic, morphogenic, and anti-apoptotic activities in a wide variety of cells, including neurons, by binding to the c-Met receptor tyrosine kinase(c-Met). HGF is one of the most potent in vitro and in vivo survival-promoting factors for neurons. For example, neurotrophic effects of HGF have been demonstrated in cultured hippocampal neurons and in cultured embryonic spinal motoneurons, and its anti-apoptotic activity in motoneurons is comparable to that of glial cell line-derived neurotrophic factor(GDNF). In the present study, the effects of HGF on motor dysfunction were examined using double transgenic mice overexpressing mutated human AR and HGF. We cross-bred AR-97Q mice with mice over-expressing the HGF. The double transgenic mice showed improvement of their motor function, body weight, lifespan. Overexpression of HDF also ameliorated motor function in the castrated male AR-97Q mice. These findings suggest that HGF over-expression ameliorates SBMA phenotypes in mice.

脊髓延髓肌萎缩症是一种遗传性运动神经元疾病。SBMA的分子基础是雄激素受体（Alt）基因中编码多聚谷氨酰胺（polyQ）序列的三核苷酸CAG重复序列的扩增。我们产生了表达全长人AR的转基因小鼠模型，该全长人AR含有在巨细胞病毒增强子和鸡β-肌动蛋白启动子控制下的24或97个CAG重复序列（AR-97 Q小鼠）。肝细胞生长因子（HGF）最初被鉴定为成熟肝细胞的有效有丝分裂原并进行分子克隆。随后的研究表明，HGF通过与c-Met受体酪氨酸激酶（c-Met）结合，在多种细胞（包括神经元）中发挥多种生物学作用，包括促有丝分裂、促运动、形态发生和抗凋亡活性。肝细胞生长因子（HGF）是体内外最有效的神经元存活促进因子之一。例如，在培养的海马神经元和培养的胚胎脊髓运动神经元中已经证明了HGF的神经营养作用，并且其在运动神经元中的抗凋亡活性与胶质细胞系衍生的神经营养因子（GDNF）相当。在本研究中，使用过表达突变的人AR和HGF的双转基因小鼠研究HGF对运动功能障碍的影响。我们将AR-97 Q小鼠与过表达HGF的小鼠杂交。双转基因小鼠的运动功能、体重、寿命均有所改善。HDF的过表达也改善了去势雄性AR-97 Q小鼠的运动功能。这些发现表明，HGF过表达改善小鼠SBMA表型。