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Recovery from the Cardiac Remodeling by Neovascularization under the Immunologic Annergy Induced by CTLA4Ig

CTLA4Ig诱导的免疫无能下新生血管形成的心脏重塑的恢复

基本信息

批准号：
11470154
负责人：
KITABATAKE Akira
金额：
$ 9.02万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470154/
关键词：
Cardiac Remodeling Angiogenesis VEGF T cells Myocyte transplantation CTLA4Ig Osteopontin CTLA41g

项目摘要

The objectives of this research project were to clarify whether it establishes the usefulness of the angiogenesis therapy on the assumption of the mechanism that in remodeling process of the failing myocardium, abnormalities in the capillary microvasculature by the angiogenesis develops in myocardial blood flow and that the cardiac function deteriorates further in the failing heart. It was demonstrated that gene expression and venule capillary densities of VEGF recovered with that in dilated cardiomyopathy model hamster, the myocardial cell density decreases for a heart failure stage, and that the capillary density decreases, while the fibrillation organization volume increases, and that it suppresses the gene expression of VEGF concomitantly that suppression of the myocardial fibrosis. It was planned that 1999 fiscal year, we introduced human angiopoietin 1 and 2 genes to the heart muscle with VEGF as a target gene. Until now, there was a problem that adenovirus, which was recognized as a foreign body. In order to inhibit costimulatory signal of T cells, AdexCTLA4Ig was developped, and the technique which induced the immunologic tolerance was induced by AdexCTLA4Ig. AdexCTLA4Ig has already made, and the extensive expression of LacZ was confirmed. The endothelial cell is induced the angiogenesis by VEGF, and activating factor angiopoietin 1 and control factor angiopoietin 2 adjust it. At present, VEGF, angiopoietin 1, angiopoietin 2 gene transfection can be done and it uses are being tried 2 each. Moreover, microvasculature construction using synchrotron radiation SPring8 with the newborn blood vessel is being analyzed, since to catch the change of the angioarchitecture in the conventional method is difficult. Altough there remain several steps to be overcome before making decision, these sophisticated studies provide original and important findings in the field of molecular cardiology.

本研究项目的目的是澄清血管生成疗法是否有用，其假设是在衰竭心肌的重塑过程中，心肌血流中因血管生成而导致毛细血管微血管异常，并且衰竭心脏的心功能进一步恶化。结果表明，在扩张型心肌病模型仓鼠中，在心力衰竭阶段，心肌细胞密度降低，毛细血管密度降低，而颤动组织体积增加，VEGF的基因表达和微静脉毛细血管密度恢复，并且抑制VEGF基因表达，从而抑制心肌纤维化。计划在1999财年，以VEGF为靶基因，将人类血管生成素1和2基因引入心肌。到目前为止，存在一个问题，即腺病毒，它被认为是异物。为了抑制T细胞的共刺激信号，开发了AdexCTLA4Ig，并通过AdexCTLA4Ig诱导免疫耐受的技术。 AdexCTLA4Ig已经制备，并且证实了LacZ的广泛表达。 VEGF诱导内皮细胞血管生成，并由激活因子血管生成素1和控制因子血管生成素2调节。目前，已可进行VEGF、血管生成素1、血管生成素2基因转染，各正在试用2个。此外，由于用传统方法很难捕捉血管结构的变化，因此正在分析使用同步辐射SPring8与新生儿血管的微血管结构。尽管在做出决定之前仍有几个步骤需要克服，但这些复杂的研究在分子心脏病学领域提供了原创且重要的发现。