Hierarchical Regulation of Multiple Angiogenic Growth Factors During 'Functional' Angiogenesis In Vivo

在本项目中，我们使用非常有效的病毒载体，即重组仙台病毒（SeV），集中于体内决定“功能性和生理性”或“非功能性和病理性”血管生成的基本机制。（1）在血管生成过程中，多种血管生成因子表达的协调调节，即“时机”和“表达水平”，血管生成因子的“时机”和“表达水平”失衡导致“病理性”血管生成。（2）碱性成纤维细胞生长因子（basicfibroblastgrowthfactor，FGF-2）是诱导“功能性”血管生成的最佳多肽之一。在此过程中，FGF-2调节多种血管生成生长因子的多步激活。（3）间充质细胞，包括周细胞、平滑肌细胞和成纤维细胞，是形成'功能性'血管生成所绝对需要的，这些发现已经发表在10多个国际公认的同行评审期刊上（Circ Res，3篇论文，J Immunol，Gene Ther，Escherichia coli Gene Ther等）。根据这些发现，我们现在开始了一个项目，即“使用表达人FGF-2基因的重组SeV治疗严重肢体缺血受试者的血管生成基因疗法的I期和IIa期临床研究”。该方案已通过机构审查委员会，目前正在接受政府基因治疗委员会的评估。目前已完成GMP级载体的制备和干预用生物危害室的建立，希望继续探索“功能性血管生成”的基本机制，并开展“血管生成基因治疗的临床试验”，以实现更有效的血管生成治疗。

In this project, we focused onto the basic mechanisms which determine 'functional and physiological' or 'non-functional and pathological' angiogenesis in vivo using extremely efficient viral vector, namely recombinant Sendai virus(SeV).We clarified that ;(1)During angiogenic process, harmonized regulation of the expression of multiple angiogenic factors, namely 'timing' and 'expression level', is required for neovessels to get their function ; unbalanced 'timing' and 'expression level' of angiogenic factors resulted in 'pathological' angiogenesis.(2)Basic fibroblast growth factor(FGF-2) is one of best polypeptide to induce 'functional' angiogenesis. During this process, FGF-2 regulates multistep activation of multiple angiogenic growth factors.(3)Mesenchymal cells, including pericytes, smooth muscle cells, and fibroblasts, are absolutely required to form 'functional' angiogenesis.These findings have been published more than 10 internationally recognized peer-reviewed journals(Circ Res,3 papers, J Immunol, Gene Ther, Hum Gene Ther, etc).According to these findings, we now started a project for "Phase I and IIa clinical study for angiogenic gene therapy using recombinant SeV expressing human FGF-2 gene to treat subjects with critical limb ischemia". The protocol has been passed the Institutional Review Board, and now under evaluation by Governmental Gene Therapy Committee. Preparation of GMP grade vectors and biohazard room for intervention have been completed.We hope to continue the research seeking the basic mechanisms of 'functional angiogenesis' as well as 'clinical trial of angiogenic gene therapy' to perform more efficient angiogenic therapeutics.