Biological functions of ternary complex factors in pancreatic beta-cells

胰腺β细胞三元复合因子的生物学功能

• 批准号: 236732209
• 负责人: Professor Dr. Gerald Thiel
• 金额: --
• 依托单位: Laboratory of Biosignaling & Therapeutics
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/236732209?language=en
• 关键词: Biological; functions; ternary; complex; factors

The research projects aims to elucidate the biological functions of ternary complex factors (TCF) in pancreatic beta-cells of transgenic mice. The TCFs interact with the serum-response factor, generating a ternary nucleoprotein complex. The TCFs are key regulators of serum-response element-mediated transcription. TCF proteins also influence transcription mediated by the transcription factor AP-1. Elk-1, a member of the TCF family of transcription factors, is activated in glucose-treated pancreatic beta-cells and has been correlated with cellular growth and/or apoptosis. We have generated conditional transgenic mice expressing dominant-negative mutant of Elk-1 in pancreatic beta-cells. The mutant interferes with DNA and SRF-binding of all TCF proteins and thus impairs the biological functions of the entire TCF family. First qRT-PCR-results obtained in the analysis of the newly generated transgenic mice revealed that beta-cell-specific expression of the dominant-negative mutant of Elk-1 reduced expression of Pdx-1 and insulin in pancreatic beta-cells. The investigation aims to elucidate the impact of transgene expression upon glucose homeostasis, insulin release, proliferation and apoptosis. In addition, TCF target genes will be identified using the microarray technology. The identification of new TCF-regulated candidate genes that may influence insulin biosynthesis and secretion, glucose homeostasis, beta-cell proliferation and cell death may open new routes to study the development of diabetes.

该研究项目旨在阐明三元复合因子（TCF）在转基因小鼠胰腺β细胞中的生物学功能。TCF与血清反应因子相互作用，产生三元核蛋白复合物。TCF是血清应答元件介导的转录的关键调节因子。TCF蛋白也影响转录因子AP-1介导的转录。Elk-1是转录因子TCF家族的成员，在葡萄糖处理的胰腺β细胞中被激活，并与细胞生长和/或凋亡相关。我们已经产生了在胰腺β细胞中表达Elk-1显性阴性突变体的条件转基因小鼠。该突变体干扰所有TCF蛋白的DNA和SRF结合，从而损害整个TCF家族的生物学功能。在新产生的转基因小鼠的分析中获得的第一个qRT-PCR结果显示，Elk-1的显性阴性突变体的β细胞特异性表达降低了胰腺β细胞中Pdx-1和胰岛素的表达。本研究旨在阐明转基因表达对葡萄糖稳态、胰岛素释放、增殖和凋亡的影响。此外，TCF靶基因将使用微阵列技术进行鉴定。新的TCF调节的候选基因，可能会影响胰岛素的生物合成和分泌，葡萄糖稳态，β细胞增殖和细胞死亡的鉴定可能会打开新的途径来研究糖尿病的发展。