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Pathophysiological analysis and gene therapy of thoracic and abdominal aortic aneurysm

胸腹主动脉瘤的病理生理分析及基因治疗

基本信息

批准号：
10470162
负责人：
ISOBE Mitsuaki
金额：
$ 5.5万
依托单位：
Tokyo Medical and Dental University (1999-2000)Shinshu University (1998)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10470162/
关键词：
Aortic aneurysm myosin heavy chain extracellular matrix atherosclerosis apoptosiss cardiac transplantation remodeling gene therapy ゲラチナーゼ in situ RT-PCR TUNEL法形質変換

项目摘要

1. The pathogenesis of aortic abdominal aneurysm (AAA) and thoracic aneurysm formation remains uncertain. Enzymes that weaken the extracellular matrix appear crucial in plaque rupture and smooth muscle cell (SMC) migration and may contribute to aneurysm formation. Matrix metalloproteinases (MMPs) degrade components of the vascular extracellular matrix and are regulated by tissue inhibitors of matrix metalloproteinases (TIMPs). SMCs may also participate in matrix remodeling through localized production of various proteinases and their inhibitors. To determine whether phenotypic modulation and proteolytic activity in vascular SMCs contributes to arterial medial degeneration, we examined Smisoforms, MMPs and TIMPs in SMCs in 17 patients with AAA who underwent surgical treatment. We clarified that balance shifted to SMemb predominance in the diseased aortas. SMemb expression is increased in aneurysm with MMP enhancement, and a significant imbalance of SMemb/SM2 and MMP/TIMP was revealed in … More rapid progression of AAA.2. The goal of the second project was to explore the possibility that gene therapy of MMPs is effective in stabilizing aortic aneurysm. We tested an efficacy and safety of gene transfer to the vessel wall by HVJ-liposome method. We used ectopically transplaned murine heart and its coronary arteries as an animal model, because of the similarity in pathogenesis of vascular lesions between chronic rejection and AAA.FITC-labeled ODN was infused into coronary arteries of explanted heart before transplantation on ice for ten minutes by HVJ-liposome method. FITC was detected on coronary arteries of transplanted heart as long as 2 weeks. Antisense bcl-x and PCNA ODN were effective in inhibition of neointimal formation in this animal model. We also used ectopic heart transplatation in monkeys to ensure the safety of this technology. E2F decoy DNA fragment was transferred to explanted heart just as the mouse model. The decoy was expressed on donor heart and recipients appeared healthy. We conclude that this technique is useful for delivery of ODN to arterial wall.3. Next step would include generation of antisense MMPs ODN or MMP ribozyme and development of an animal model of AAA.The effect of MMP inhibition by gene therapy could by evaluated using these experimental systems. Less

1.腹主动脉瘤（AAA）和胸主动脉瘤形成的发病机制仍然不确定。削弱细胞外基质的酶在斑块破裂和平滑肌细胞（SMC）迁移中起关键作用，并可能导致动脉瘤形成。基质金属蛋白酶（MMP）降解血管细胞外基质的成分，并受基质金属蛋白酶组织抑制剂（TIMP）的调节。SMC也可以通过局部产生各种蛋白酶及其抑制剂参与基质重塑。为了确定血管SMC的表型调节和蛋白水解活性是否有助于动脉中膜变性，我们检测了17例接受手术治疗的AAA患者SMC中的Smisoforms、MMPs和TIMPs。我们澄清了在患病的乳腺癌中，平衡转移到SMemb占优势。在MMP增强的动脉瘤中SMemb表达增加，并且SMemb/SM 2和MMP/TIMP的显著失衡在MMP增强的动脉瘤中显示。 ...更多信息 AAA.2的快速进展。第二个项目的目标是探索MMPs基因治疗在稳定主动脉瘤中有效的可能性。我们用HVJ-脂质体法检测了基因转移到血管壁的有效性和安全性。由于慢性排斥反应与AAA血管病变的发病机制相似，我们采用小鼠异位心脏及其冠状动脉作为动物模型，在移植前用HVJ-脂质体法将FITC标记的ODN灌注于小鼠异位心脏冠状动脉内10分钟。移植心脏冠状动脉上可检测到FITC，时间长达2周。bcl-x反义核酸和PCNA反义核酸均能有效抑制新生内膜的形成。我们还在猴子身上进行了异位心脏移植，以确保这项技术的安全性。与小鼠模型一样，将E2 F诱饵DNA片段转移到外植心脏中。诱饵在供体心脏上表达，受体看起来健康。我们的结论是，这种技术是有用的ODN输送到动脉壁。下一步的工作是制备反义MMP ODN或MMP核酶，并建立AAA动物模型，利用这些实验系统可以评价MMP基因治疗的效果。少