Development of therapeutics using interleukin-4 (IL-4) mutein in atherosclerotic mouse model showing Th1-dominant immune response

在显示 Th1 主导免疫反应的动脉粥样硬化小鼠模型中使用白细胞介素 4 (IL-4) 突变蛋白开发治疗方法

• 批准号: 16590328
• 负责人: KATO Seiya
• 金额: $ 2.41万
• 依托单位: University of the Ryukyus (2006-2007)Kurume University (2004-2005)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16590328/
• 关键词: atherosclerosis; inflammation; Th1 response; cytokine; interleukin-4 (IL-4); mouse; cell culture; Thl反応

Inflammatory process of atherosclerosis and its therapeutic implication have been studied. LPA (Lysophosphatidic acid) showed mitogenic activity in the cultured smooth muscle cells as well as induction of NADPH-dependent intracellular oxidative stress, rac-1 (small GTPase) activation, and MCP-1 expression, of which pathway was inhibited by antioxidant and statin. Such in vitro experiments suggested an inflammatory phenotype of vascular cells. Administration of soluble INF_<-γ> receptor in ApoE knockout mice resulted in the suppression of atherogenesis. Moreover, STAT6 knockout mice (B6 backbone) showed not only Th1 shift in the immunological response but the phenotypes of obesity and glucose tolerance, suggesting a close relationship between inflammatory, immunological process and atherosclerosis or metabolic risk factors. Wild type mouse IL-4 gene and its specific cell oriented mutein, Q116E, were sub-cloned into adenovirus-derive expression (shuttle) vector. Primary mouse vascular cells were tested for the changes in inflammatory phenotypes. Development of replication-deficient adenoviral vector was attempting for in vivo experiments. These results further highlighted the importance of inflammatory process of atherosclerosis and suggest the therapeutic implications. We gratefully appreciate for supporting our work and continue to make our best effort to dissolve the pathological problems in human cardiovascular diseases.

研究了动脉粥样硬化的炎症过程及其治疗意义。LPA（溶血磷脂酸）在培养的平滑肌细胞中表现出促有丝分裂活性以及诱导NADPH依赖的细胞内氧化应激、rac-1（小GTdR）活化和MCP-1表达，抗氧化剂和他汀类药物抑制该途径。这样的体外实验表明血管细胞的炎性表型。可溶性INF_<-γ>受体可抑制ApoE基因敲除小鼠的动脉粥样硬化形成。此外，STAT 6敲除小鼠（B6骨架）不仅表现出免疫应答中的Th 1移位，而且表现出肥胖和葡萄糖耐量的表型，表明炎症、免疫过程与动脉粥样硬化或代谢危险因素之间存在密切关系。将野生型小鼠IL-4基因及其特异性细胞定向突变蛋白Q116 E亚克隆到腺病毒衍生的表达载体（穿梭）中。检测原代小鼠血管细胞的炎症表型变化。复制缺陷型腺病毒载体的开发正在尝试用于体内实验。这些结果进一步强调了动脉粥样硬化炎症过程的重要性，并提出了治疗意义。我们衷心感谢您对我们工作的支持，并将继续为解决人类心血管疾病的病理问题而努力。

项目成果

Experimental gene therapy using p21/Waf1 gene for esophageal squamous cell carcinoma by gene gun technology.

通过基因枪技术使用p21/Waf1基因治疗食管鳞状细胞癌的实验性基因治疗。

• 发表时间: 2004
• 期刊: Int J Mol Med 14・4
• 作者: Sugimachi K;et al.;Tanaka Y
• 通讯作者: Tanaka Y

Effects of thioredoxin on established airway remodeling in a chronic antigen exposure asthma model

• DOI: 10.1016/j.bbrc.2007.06.019
• 发表时间: 2007-08-31
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Imaoka, Haruki;Hoshino, Tomoaki;Aizawa, Hisamichi
• 通讯作者: Aizawa, Hisamichi

Advanced glycation end-products regulate proliferation and differentiation of human mesenchymal stem cells.

高级糖基化终产物调节人间充质干细胞的增殖和分化。

• 发表时间: 2004
• 作者: Kaneyuki U;Kato S;Ueda S;Yamagishi S;Inagaki Y;Yoshimura J;Imaizumit;Okuda S.;Maeda M;Kume S
• 通讯作者: Kume S

AGEs activate mesangial TGF-β-Smad signaling via an angiotensin II type I receptor interaction

• DOI: 10.1111/j.1523-1755.2004.66004.x
• 发表时间: 2004-12-01
• 期刊: KIDNEY INTERNATIONAL
• 影响因子: 19.6
• 作者: Fukami, K;Ueda, S;Okuda, S
• 通讯作者: Okuda, S

Regulation of vascular smooth muscle proliferation and migration by beta2-chimaerin, a non-protein kinase C phorbolester receptor.

β2-chimaerin（一种非蛋白激酶 C 佛波酯受体）对血管平滑肌增殖和迁移的调节。

• 发表时间: 2006
• 期刊: Int J Mol Med 17
• 作者: Maeda M;Kato S;Fukushima S;Kaneyuki U;Fujii T;Kazanietz MG;Oshima K;Shigemori M.;Matsuguma K;Hanada T;Maeda M
• 通讯作者: Maeda M