GENE THERAPY TO INDUCE THERAPEUTIC ANGIOGENESIS

这些研究分为组织培养实验和临床前研究。 动物研究。体外实验有以下目标： (1)研究胰岛素样生长因子-1(IGF-1)对血管内皮细胞生长的影响。 血管内皮细胞功能及其与IGF-1的相互作用 血管生成生长因子。结果表明，IGF-1单独或在 联合应用血管内皮细胞生长因子对人体无影响 微血管内皮细胞增殖。相比之下，IGF-1和Basic 成纤维细胞生长因子具有显著的协同作用。 内皮细胞增殖。(2)阐明 酸化对内皮细胞功能的影响。结果表明， 高碳酸中毒抑制内皮细胞增殖 内皮细胞生长促进内皮细胞有丝分裂原分泌 在酸性条件下。(3)确定低氧对小鼠的影响。 整合素在内皮细胞中的表达。结果表明，低氧 相比之下，对降低αvbeta5的表达有显著效果 αvbeta5和β1的表达均不受缺氧的影响。这个 体内实验有以下目标：(1)确定 急性期侧支血流是否发生发展 后肢缺血与年龄有关。结果显示，腓肠肌 31P核磁共振评价2月龄和20月龄小鼠肌肉的生物能量恢复 老年大鼠股动脉夹层后1天和7天的损伤 幼小的动物。(2)确定腺病毒介导的重组体、 分泌型酸性成纤维细胞生长因子(AdCMV.sp+aFGF1-154)基因 转移具有致癌的潜力。结果表明，NIH3T3细胞 感染AdCMV.sp+aFGF1-154表现出短暂的生长优势，但 不是一个稳定的转变。(3)确定AdCMV.sp+aFGF1-154 在治疗急性心肌梗死方面具有治疗潜力 缺血症。结果表明，心肌内注射阿魏酸甘油酯 AdCMV.sp+aFGF1-154在无慢性缺血条件下诱导血管生成 减少急性心肌梗死的危险区域 冠状动脉结扎术。

These studies are divided into tissue culture experiments and preclinical animal studies. The in vitro experiments have the following objectives: (1) to characterize the effect of insulin-like growth factor 1 (IGF-1) on endothelial cell function and the interaction of IGF-1 with other angiogenic growth factors. The results show that IGF-1 alone or in combination with vascular endothelial growth factor has no effect on human microvascular endothelial cell proliferation. In contrast IGF-1 and basic fibroblast growth factor have a significant synergistic effect on endothelial cell proliferation. (2) to elucidate the effect of acidification on endothelial cell function. The result show that hypercarbic acidosis inhibits endothelial cell proliferation despite an increased endothelial mitogen secretion from the endothelial cells grown in acidotic conditions. (3) to determine the effect of hypoxia on integrin expression in endothelial cells. The results show that hypoxia has a significant effect to decrease alphavbeta5 expression, in contrast neither alphavbeta5 nor beta 1 expression were modulated by hypoxia. The in vivo experiments have the following objectives: (1) to determine whether the development of collateral blood flow in response to acute hindlimb ischemia is age-dependent. The results show that gastrocnemius muscle bioenergetic recovery evaluated by 31p NMR in 2 and 20 month old rats 1 and 7 days after femoral artery dissection is impaired in old vs young animals. (2) to determine whether adenovirus-mediated recombinant, secreted acidic fibroblast growth factor (AdCMV.sp+aFGF1-154) gene transfer has a tumorigenic potential. The results show that NIH 3T3 cells infected with AdCMV.sp+aFGF1-154 exhibit a transient growth advantage but not a stable transformation. (3) to determine whether AdCMV.sp+aFGF1-154 has a therapeutic potential in the treatment of acute myocardial ischemia. The results show that the intramyocardial injection of AdCMV.sp+aFGF1-154 in the absence of chronic ischemia induces angiogenesis and decreases the risk region for myocardial infarction upon acute coronary artery ligation.