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Development of inhibitors for the activation of cardiovascular interstitial ceils

心血管间质细胞激活抑制剂的开发

基本信息

批准号：
11357007
负责人：
NAGAI Ryozo
金额：
$ 14.05万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11357007/
关键词：
cardiovascular system interstitium transcription factor therapy 間質細胞心血管系活性化 klotho BTEB2 DNAチップ

项目摘要

Activation of interstitial cells of the cardiovascular system plays pivotal roles in initiation and progression of cardiac and vascular diseases including cardiac hypertrophy, heart failure, and atherosclerosis. Responding to external stresses, interstitial cells such as fibroblasts and smooth muscle cells promote structural remodeling by producing growth factors, extracellular matrices, and matrix metalloproteases. Thus, drugs that inhibit activation of these cell-types would have potential for novel treatment of cardiovascular diseases. However, little has been known regarding transcriptional control mechanisms of the activation of the cells. The goals of the present studies were : 1) to identify compounds that inhibited activation of smooth muscle cells by modifying the Junction of transcription factors, 2) to identify transcription factors involved in activation of cardiac interstitial cells, and 3) to generate transgenic rats secreting ageing-related protein Klotho, which is though to play a protective role for the cardiovascular system in ageing, into milk. We identified several compounds that could inhibit activation of smooth muscle cells and examined their activities in cultured smooth muscle cells and in vivo. We analyzed expression patterns of genes in activation of cardiac interstitial cells by angiotensin n and found several transcription factors including BTEB2 that induced by angiotensin II. We generated a Klotho transgene construct driven by the lactoalbumin promoter and obtained transgenic rat lines.

心血管系统间质细胞的活化在心脏和血管疾病（包括心脏肥大、心力衰竭和动脉粥样硬化）的发生和发展中起关键作用。间质细胞如成纤维细胞和平滑肌细胞对外部应激作出反应，通过产生生长因子、细胞外基质和基质金属蛋白酶促进结构重塑。因此，抑制这些细胞类型的激活的药物将具有用于心血管疾病的新治疗的潜力。然而，很少有人知道有关的细胞激活的转录控制机制。本研究的目的是：1）鉴定通过修饰转录因子的连接来抑制平滑肌细胞活化的化合物，2）鉴定参与心脏间质细胞活化的转录因子，和3）产生分泌衰老相关蛋白Klotho的转基因大鼠，Klotho被认为在衰老中对心血管系统起保护作用。我们鉴定了几种可以抑制平滑肌细胞活化的化合物，并在培养的平滑肌细胞和体内检测了它们的活性。我们分析了血管紧张素Ⅱ激活心肌间质细胞的基因表达模式，发现了包括BTEB 2在内的几种血管紧张素Ⅱ诱导的转录因子。我们生成了由乳白蛋白启动子驱动的Klotho转基因构建体，并获得了转基因大鼠品系。