Molecular Pathophysiological Study on Endothelial Function Occurring during Vascular Remodeling

血管重塑过程中内皮功能的分子病理生理学研究

• 批准号: 13307009
• 负责人: SUEISHI Katsuo
• 金额: $ 35.36万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13307009/
• 关键词: vascular remodeling; atherosclerosis; angiogenesis; angiogenic hierarchy; FGF-2; SeV; Gene transfer; tissue stem cell; 血管内皮細胞; 血管平滑筋細胞; ウイルスベクター; 遺伝子治療; VEGF; 血管新生病

1.Endothelial function in physiological and pathological vascular remodelingFrom studies concerning atherosclerosis, mechanism of functional angiogenesis, differentiation mechanism of hepatic stem cell, the main results obtained were as follows :1)Atherosclerosis and angiogenesis : intimal neovascularization related to VEGF-A and -C expression was equivalent to a histopathological hallmark of active atherogenesis, and we propose "inflammation-repair hypothesis" for atherogenesis.2)Molecular mechanism of functional angiogenesis : FGF-2 hierarchically enhanced the expression of VEGF,HGF,PDGF and others in a hypoxic tissues, leading to the integrated angiogenesis associated with structural and functional interaction between endothelial-pericytes(smooth muscle cells).3)Differentiation mechanism of hepatic stem cells : FLK-1-positive cells in mouse fetuses possessed the pluripotent differentiation activities into hepatocytes and bile ducts, and blood vessels under HGF+EGF and VEGF+PDGF-BB stimulation, respectively.2.Biological properties of novel gene transfer vectors and their clinical applicationUsing recombinant SeV and SIV vectors with several reporter and target genes(FGF-1,-2,-10,VEGF-A,PEDF,sprouty-2,soluble PDGF receptor etc), biological and pathbphysiological characteritics of spatial and time-sequential transfer/expression efficacy of these vectors were analyzed and we are exploiting the novel strategies on gene therapy.

通过对动脉粥样硬化、功能性血管生成机制、肝干细胞分化机制等方面的研究，得出以下主要结果：1)动脉粥样硬化与血管生成：与血管内皮生长因子-A、-C表达相关的血管内膜新生相当于动脉粥样硬化形成活跃的组织病理学标志，提出了动脉粥样硬化形成的“炎症-修复假说”。2)功能性血管生成的分子机制：在缺氧组织中，成纤维细胞生长因子-2促进血管内皮细胞生长因子、肝细胞生长因子、血小板衍生生长因子等的表达。3)肝干细胞分化机制：小鼠胎肝Flk-1阳性细胞在HGF+EGF和VEGF+PDGF-BB刺激下分别具有向肝细胞、胆管和血管的多向分化活性。2.新型基因转移载体的生物学特性及其临床应用分析了这些载体的空间和时序转移/表达效率的生物学和病理生理特性，并正在探索基因治疗的新策略。

项目成果

Nakashima Y, Chen Y-X, Kinukawa N, Sueishi K.: "Distributions of diffuse intimal thickening in human arteries : Preferential expression in atherosclerosis-prone arteries from an early age."Virchow Arch. 441. 279-288 (2002)

Nakashima Y、Chen Y-X、Kinukawa N、Sueishi K.：“人类动脉中弥漫性内膜增厚的分布：从小就在易发生动脉粥样硬化的动脉中优先表达。”Virchow Arch。

Ameri A, et al.: "Myocardial fibrosis in mice with over-expression of human blood coagulation factor IX : Myocardial infarction model"Blood. (in press).

Ameri A 等人：“人类凝血因子 IX 过度表达的小鼠心肌纤维化：心肌梗塞模型”血液。

Ikeda Y, et al.: "Recombinant Sendai virus-mediated gene transfer to the retinal tissue of adult rats : efficient gene transfer by brief exposure"Exp Eye Res. (in press).

Ikeda Y 等人：“重组仙台病毒介导的基因转移到成年大鼠的视网膜组织：通过短暂暴露进行有效的基因转移”Exp Eye Res。

Ikeda Y, et al.: "Simian immunodeficiency virus-based lentivirus vactor for retinal gene transfer : a preclinical safety study in adult rats."Gene Therapy. 10(14). 1161-1169 (2003)

Ikeda Y 等人：“用于视网膜基因转移的基于猿免疫缺陷病毒的慢病毒载体：成年大鼠的临床前安全性研究。”基因治疗。

Nakashima Y, et al.: "Distributions of diffuse intimal thickening in human arteries : Preferential expression in atherosclerosis-prone arteries from an early age."Virchow Arch. 441. 279-288 (2002)

Nakashima Y 等人：“人类动脉中弥漫性内膜增厚的分布：从小就在易发生动脉粥样硬化的动脉中优先表达。”Virchow Arch。