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.

血管内皮细胞在调节血管张力、血管生长、平滑肌增殖、止血、血管生成和血管生成等方面发挥着重要作用。然而，人们对这些事件背后的基因调控机制知之甚少。内皮素-1(ET-1)是一种强大的血管收缩多肽，主要以内皮细胞特异性的方式表达，在健康和疾病中的表达都受到严格的调控。根据我的初步数据，我认为VEZF1/DB1是一个锌指转录因子，是一种内皮细胞特异性的转录因子，调节ET-1的表达。我在ET-1启动子最小的VEZF1/DB1反应元件(顺式作用元件)上表征了VEZF1/DB1参与DNA：蛋白质复合体的作用。我打算用含有在这个位置突变的启动子的转基因小鼠来测试这个元件在ET-1基因发育表达中的重要性。我还将通过酵母双杂交筛选鉴定与VEZFI/DB1参与调控ET-1基因表达的潜在相互作用伙伴，并测试这些相互作用伙伴对ET-1表达的重要性。这些研究将为健康和疾病中潜在的内皮基因表达机制提供重要的新见解。