TRANSCRIPTION FACTORS AND THE ENDOCRINE PANCREAS

转录因子和内分泌胰腺

• 批准号: 6381475
• 负责人: JOEL F HABENER
• 金额: $ 25.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-16 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6381475
• 关键词: DNA binding protein; DNA footprinting; apoptosis; cell differentiation; cell growth regulation; developmental genetics; diabetes mellitus; disease /disorder etiology; gene expression; genetic transcription; genetically modified animals; histogenesis; hormone receptor; hormone regulation /control mechanism; hyperglycemia; incretin hormone; laboratory mouse; pancreas; pancreatic islets; transcription factor

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.

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。