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

Effect of siRNA targeting SHP-1 on angiogenesis in hindlimb ischemia

靶向SHP-1的siRNA对后肢缺血血管生成的影响

基本信息

批准号：
18590817
负责人：
SUGANO Masahiro
金额：
$ 2.49万
依托单位：
Kyushu 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-18590817/
关键词：
angiogenesis tyrosine phosphatases SHP-1 genr therapy 遺伝子治療 Protein tyrosine phosphatase angiogenesis Peripheral ischemic disease gene therapy

项目摘要

Vascular endothelial growth factor (VEGF) promotes the growth of vascular endothelial cells and the development of new blood vessels through interaction with VEGF receptor-2 (KDR/flk-1). The binding of VEGF to KDR/flk-1 induces conformational changes in the receptor, followed by dimerization and autophosphorylation of the tyrosine residues. The phosphorylated KDR/flk-1 can be a substrate for intracellular protein tyrosine phosphatases. SHP-1 , a cytoplasmic protein tyrosine phosphatase that contain two Src homology 2 domains in its N-terminal half, interacts with activated cytokine, growth factor, and antigen receptors and plays a negative regulatory role in signal transduction pathways by dephosphorylation of the receptors or receptor substrates to which it binds. Thus, therapeutic angiogenesis designed to inhibit expression of SHP-1 would be beneficial in hindlimb ischemia. Here we report that siRNA targeting SHP-1 activates KDR/flk-1 and accelerates angiogenesis in a rat model of hindlimb ischemia. Upon injection to the ischemic adductor muscle, vector-based siRNA reduced SHP-1, increased phosphorylation of KDR/flk-1, and markedly increased capillary density. Our data demonstrate in vivo the potential use of siRNA targeting SHP-1 as therapy for peripheral ischemic diseases.

血管内皮生长因子（Vascular endothelial growth factor， VEGF）通过与VEGF受体-2 （KDR/flk-1）相互作用，促进血管内皮细胞的生长和新生血管的形成。VEGF与KDR/flk-1的结合诱导受体的构象变化，随后是酪氨酸残基的二聚化和自磷酸化。磷酸化的KDR/flk-1可以作为细胞内蛋白酪氨酸磷酸酶的底物。SHP-1是一种细胞质蛋白酪氨酸磷酸酶，其n端一半含有两个Src同源2结构域，可与活化的细胞因子、生长因子和抗原受体相互作用，并通过使其结合的受体或受体底物去磷酸化，在信号转导途径中发挥负调控作用。因此，设计抑制SHP-1表达的治疗性血管生成将有利于后肢缺血。本研究报告了在大鼠后肢缺血模型中，靶向SHP-1的siRNA激活KDR/flk-1并加速血管生成。注射到缺血内收肌后，基于载体的siRNA降低了SHP-1，增加了KDR/flk-1的磷酸化，并显著增加了毛细血管密度。我们的数据在体内证明了靶向SHP-1的siRNA作为外周缺血性疾病治疗的潜在用途。