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Gene analysis of hypertension and development of new therapy

高血压基因分析及新疗法开发

基本信息

批准号：
07407021
负责人：
OGIHARA Toshio
金额：
$ 19.39万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

项目摘要

1. Gene analysis of hypertensionWe examined the association between variants in the core promotor element 1 (AGCE1) of the human angiotensinogen gene, which acts as a critical regulator of angiotensinogen transcription. The results obtained was that C-18T polymorphism in AGCE1 is a genetic risk factor for essential hypertension in Japanese. These results suggest that dysfunction of promortor element of angiotensinogen gene may be related to the genetic pathogenesis of hypertension.2. Gene therapy of cardiovascular diseasesThe transcriptional factor NFkB plays a pivotal role in the coordinated transactivation of cytokine and adhesion molecule genes that might be involved in myocardial damage after ischemia and reperfusion. Then we transfected synthetic double-stranded DNA with high affinity for NFkB before or after the cardiac ischemia in rats. We showed that the first successful in vivo tranfer of NFkB decoy oligodeoxynucleotides to reduce the extent of myocardial infraction following reperfusion, providing a new therapeutic strategy for myocardial infarction.3.Pathogenesis of cascular remodelingWe conducted histopathological study on the atheroscleosis in human coronary arteries. In the culpit region of coronary atherosclerosis, we showed over-expression of angiotensinogen and angiotensin converting-enzyme. We showed the direct evidence of the role of the tissue-renin angiotensin system in the coronary-aterosclerosis.

1.高血压的基因分析我们检查了人类血管紧张素原基因核心启动子元件1（AGCE1）变异之间的关联，该基因是血管紧张素原转录的关键调节因子。获得的结果是AGCE1的C-18T多态性是日本人原发性高血压的遗传危险因素。这些结果提示血管紧张素原基因启动子元件的功能障碍可能与高血压的遗传发病有关。 2．心血管疾病的基因治疗转录因子NFkB在细胞因子和粘附分子基因的协调反式激活中发挥着关键作用，这些基因可能参与缺血和再灌注后的心肌损伤。然后我们在大鼠心脏缺血之前或之后转染对 NFkB 有高亲和力的合成双链 DNA。我们首次成功体内转移NFkB诱饵寡脱氧核苷酸来降低再灌注后心肌梗死的程度，为心肌梗死的治疗提供了新的策略。3.血管重构的发病机制我们对人类冠状动脉粥样硬化进行了组织病理学研究。在冠状动脉粥样硬化的罪魁祸首区域，我们发现血管紧张素原和血管紧张素转换酶过度表达。我们展示了组织肾素血管紧张素系统在冠状动脉粥样硬化中作用的直接证据。