Groucho co-repressors in the regulation of pancreatic islet development

项目摘要 1型和2型糖尿病的定义特征是产生胰岛素的β细胞数量和功能丧失 (T1D和T2 D），影响美国超过3000万人。细胞机制， 导致这种疾病的原因仍然未知，尽管目前正在进行重要的研究，以了解 β细胞的发育和功能，以最终提高我们对疾病的认识，并产生有效的 糖尿病的治疗方法在这一领域的许多工作已经描述了转录因子是必要的 在这些过程中调节基因表达。然而，转录因子并不单独起作用， 调节基因表达;其他因素，如辅激活因子和辅抑制因子，也相互作用和影响 转录因子的活性，以允许激活或抑制靶基因。有一组蛋白质 与转录因子相关的是Groucho相关基因（GRG）家族的共阻遏物。GRG不直接结合 相反，它们被一系列转录因子招募到DNA中。GRG促进对 通过募集表观遗传修饰剂如HDAC来沉默基因表达来靶向基因。最近的研究 已经表明，GRG介导的基因调控机制可能不是那么简单， GRG的功能在细胞与细胞和上下文相关的方式上不同。GRG已经被证明与 胰腺和其他生物系统中的关键胰腺转录因子。GRG 3的相互作用 NKX2.2是胰腺转录因子，通过抑制非β细胞，是β细胞发育所必需的。 程序. GRG还与其他胰腺转录因子相互作用，如其他胰腺转录因子中的NKX6.1和PAX 6。 这表明GRG可能在β细胞发育过程中调节多种转录因子的活性 和功能初步数据表明，胰腺中Grg 3的缺失导致高血糖症， 小鼠内分泌细胞数量的改变。总之，这些数据表明GRG 3在β细胞中是重要的。 发展和功能，虽然GRG在这些过程中的分子机制并不完全 明白在本论文中，我将阐明GRG转录活性在调控细胞凋亡中的作用机制， β细胞身份和功能的研究。

Project Summary Loss of insulin-producing β cell number and function, the defining characteristics of Type 1 and Type 2 diabetes (T1D and T2D, respectively), affects over 30 million people in the United States. The cellular mechanisms that lead to this disease remain unknown, although significant research is currently ongoing to understand the development and function of β cells to ultimately advance our knowledge of the disease and generate effective treatments for diabetes. Much of the work in this field has described the transcription factors that are necessary for regulating gene expression during these processes. However, transcription factors do not act alone to regulate gene expression; other factors, such as co-activators and co-repressors, also interact with and influence transcription factor activity to allow activation or repression of target genes. One group of proteins that interact with transcription factors are the Groucho-related gene (GRG) family of co-repressors. GRGs do not bind directly to DNA – instead they are recruited to DNA by an array of transcription factors. GRGs promote repression of target genes by recruiting epigenetic modifiers, such as HDACs, to silence gene expression. Recent studies have shown that the mechanism of GRG-mediated gene regulation may not be this straight-forward and that the function of GRGs differ in cell-to-cell and context-dependent manners. GRGs have been shown to interact with critical pancreas transcription factors in the pancreas and in other biological systems. The interaction of GRG3 with NKX2.2, a pancreas transcription factor, is necessary for β cell development by repressing non-β cell programs. GRGs also interact with other pancreas transcription factors, such as NKX6.1 and PAX6 in other contexts, suggesting that GRGs may modulate activity of multiple transcription factors during β cell development and function. Preliminary data demonstrates that loss of Grg3 in the pancreas results in hyperglycemia and alterations in endocrine cell numbers in mice. Together, these data indicate that GRG3 is important in β cell development and function, although the molecular mechanism of GRGs in these processes is not fully understood. In this proposal, I will elucidate the mechanism of GRG transcriptional activity in the regulation of β cell identity and function using in vivo and in vitro approaches.