TRANSCRIPTION FACTORS AND THE ENDOCRINE PANCREAS

描述：（改编自申请人的摘要）β细胞质量为 由β细胞死亡（凋亡）和 新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）发生一次转变， 细胞凋亡和新的β细胞的形成，因为它们从 位于胰管中的祖细胞。申请人提出一项 “转录因子假说”作为糖尿病的原因。这一假设 指出，特定的转录蛋白，调节表达， 胰腺发育过程中的特定基因，负责β细胞 新生和凋亡，这些蛋白质的功能失调可能会减少 β细胞的生长和功能。申请人已经鉴定了两种这样的蛋白质 参与新生：同源结构域蛋白IDX-1和Pou同源结构域 蛋白质Brain 4作为β细胞和α细胞发育的关键调节因子， 分别肠促胰岛素激素胰高血糖素样肽似乎 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/EBP β和CHOP， 似乎参与细胞培养模型中β细胞的凋亡， 体外和通过小鼠体内的遗传操作。申请人认为 对IDX-1、Brn 4、C/EBP β和 CHOP在胰腺发育、胰岛细胞新生和 细胞凋亡将为未来治疗药物的开发提供机会 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.