TRANSCRIPTION FACTORS AND THE ENDOCRINE PANCREAS

转录因子和内分泌胰腺

• 批准号: 6517560
• 负责人: JOEL F HABENER
• 金额: $ 26.57万
• 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/6517560
• 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：（根据申请人的摘要进行了改编）beta细胞质量是 由β细胞死亡率（凋亡）和 新β细胞的诞生（新生成）。在老鼠和老鼠胰的中 由于β细胞质量大约每30天（每天2-3％）进行一次 凋亡和新β细胞的形成，它们与众不同 祖细胞位​​于胰管中。申请人建议 “转录因子假设”是糖尿病的原因。这个假设 指出特定的转录蛋白调节 胰腺发育过程中的特定基因负责β细胞 新生成和凋亡以及这些蛋白质的故障可能会减少 β细胞的生长和功能。申请人已经确定了两个这样的蛋白质 参与新生成：同源域蛋白IDX-1和POU - 家庭域 蛋白质脑4作为β细胞和α细胞发育的关键调节剂， 分别。肠降直泌蛋白激素胰高血糖素样肽似乎 刺激IDX-1的表达和β细胞的新作用。我们有 还确定了两个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 体内小鼠的遗传操纵。申请人认为 对IDX-1，BRN4，C/EBPBETA和 在胰腺发育，胰岛细胞新发生和 凋亡将为未来治疗的发展提供机会 治愈糖尿病的方法。