Mechanism of Regulation of Endothelin-1 Gene

Endothelin-1基因的调控机制

• 批准号: 6538094
• 负责人: JULIUS EGEDE AITSEBAOMO
• 金额: $ 5.01万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6538094
• 关键词: developmental genetics; endothelin; gene expression; genetic regulation; genetic regulatory element; genetically modified animals; laboratory mouse; postdoctoral investigator; transcription factor; vascular endothelium; yeast two hybrid system

The vascular endothelium plays a critical role in regulation of vascular tone, vessel growth, proliferation of smooth muscle, hemostasis, vasculogenesis and angiogenesis. However, little is known about the mechanisms of gene regulation that underlie these events. Endothelin-1 (ET-1), a potent vasoconstrictor peptide, is expressed predominantly in an endothelial cell-specific fashion, and its expression is tightly regulated both in health and in disease. Based on my preliminary data, I propose that VEZFl/DB1, a zinc finger transcription factor, is an endothelial cell-specific transcription factor that regulates the expression of ET-1. I have characterized the participation of VEZFl/DB1 in DNA:protein complexes at the minimal VEZF1/DB1 response element (cis-acting element) in the ET-1 promoter. I intend to test the importance of this element in developmental expression of ET- 1 gene using transgenic mice containing a promoter construct mutated at this site. I will also identify and characterize potential interacting partners that participate with VEZFI/DB1 in regulating the expression of ET-1 gene via a yeast two-hybrid screen, and test the importance of these interaction partners on ET-1 expression. These studies should provide important new insight into the mechanisms underlying endothelial gene expression in health and disease.

血管内皮在调节血管张力，血管生长，平滑肌的增殖，止血，血管生成和血管生成中起着至关重要的作用。但是，对这些事件的基因调节的机制知之甚少。内皮素-1（ET-1）是一种有效的血管收缩肽，主要以内皮细胞特异性的方式表达，其表达在健康和疾病中都受到严格调节。根据我的初步数据，我建议VEZFL/DB1是一种锌指转录因子，是一种调节ET-1表达的内皮细胞特异性转录因子。我已经表征了VEZFL/DB1参与DNA：最小VEZF1/DB1响应元件（顺式作用元件）在ET-1启动子中的蛋白质复合物。我打算使用含有在该位点突变的启动子构建体的转基因小鼠来测试该元素在ET-1基因发育表达中的重要性。我还将确定并表征与VEZFI/DB1参与的潜在相互作用伙伴通过酵母两种杂交筛选来调节ET-1基因的表达，并测试这些相互作用伙伴在ET-1表达上的重要性。这些研究应提供对健康和疾病中内皮基因表达的机制的重要新见解。