TRANSCRIPTION FACTORS AND THE ENDOCRINE PANCREAS

描述：(改编自申请人的摘要)β细胞质量是 由β细胞死亡率(细胞凋亡率)和 新的β细胞的诞生(新生)。在大鼠和小鼠的胰腺中 β细胞团大约每30天(2-3%/天)翻一次，原因是 分化过程中的细胞凋亡和新的β细胞的形成 祖细胞位于胰管内。申请人提出一项 “转录因子假说”是导致糖尿病的原因之一。这一假设 声明特定的转录蛋白，调节基因表达 在胰腺发育过程中的特定基因，负责β细胞 新生和细胞凋亡以及这些蛋白的功能障碍可能会减少 β细胞的生长和功能。申请人已经鉴定出两种这样的蛋白质 参与新生：同源结构域蛋白IDX-1和POU-同源结构域 蛋白质Brain4作为β细胞和阿尔法细胞发育的关键调节因子， 分别进行了分析。肠内胰岛素激素类胰升糖素多肽似乎 刺激IDX-1的表达和β细胞的新生。我们有 还鉴定了两种bZIP(亮氨酸拉链)蛋白，C/EBPbeta和CHOP， 在细胞培养模型中似乎参与了β细胞的凋亡 通过在体外和体内对小鼠的遗传操作。申请人认为 对IDX-1、Brn4、C/EBPβ和 CHOP在胰腺发育、胰岛细胞新生和 细胞凋亡将为未来治疗的发展提供机会 治疗糖尿病的方法。

DESCRIPTION: (Adapted from the applicant's abstract) The beta-cell mass is determined by the balance between the rates of beta-cell death (apoptosis) and the birth of new beta-cells (neogenesis). In the rat and mouse pancreas the beta-cell mass turns over approximately every 30 days (2-3%/day) due to apoptosis and the formation of new beta-cells as they differentiate from progenitor cells located in the pancreatic ducts. The applicant proposes a "transcription factor hypothesis" as a cause of diabetes. This hypothesis states that specific transcriptional proteins, that regulate the expression of specific genes during pancreas development, are responsible for beta-cell neogenesis and apoptosis and that malfunctioning of these proteins may curtail beta-cell growth and function. The applicant has identified two such proteins involved in neogenesis: the homeodomain protein IDX-1 and the Pou-homeodomain protein Brain4 as key regulators of beta-cell and alpha-cell development, respectively. The intestinal incretin hormone glucagon-like peptide appears to stimulate the expression of IDX-1 and the neogenesis of beta-cells. We have also identified two bZIP (leucine zipper) proteins, C/EBPbeta and CHOP, that appear to participate in the apoptosis of beta-cells in cell culture models in vitro and by genetic manipulations of mice in vivo. The applicant believes that a fundamental understanding of how the expression of IDX-1, Brn4, C/EBPbeta and CHOP are regulated during pancreas development, islet cell neogenesis and apoptosis will provide opportunities for the development of future therapeutic approaches for the cure of diabetes.