Metabolic consequences of securin disruption

securin 破坏的代谢后果

• 批准号: 7008190
• 负责人: SHLOMO MELMED
• 金额: $ 31.6万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7008190
• 关键词: Metabolic; consequences; securin; disruption

DESCRIPTION (provided by applicant): Cell cycle-dependent securin proteins regulate sister chromatid separation by inhibiting separin function. We isolated and have characterized pituitary tumor transforming gene (PTTG) from rat pituitary tumor cells, and PTTG is functionally homologous to yeast securin. PTTG is overexpressed in several tumor types, and also in some normal replicating tissues (including testis, lympocytes). When the PTTG gene was deleted, resultant knockout mice were viable, fertile and exhibited splenic and testicular hypoplasia and thrombocytopenia. Surprisingly, after 6 months, male PTTG -/- mice do not gain weight, develop profound hyperglycemia, hypo-insulinemia, and hypo-leptinemia with intact insulin sensitivity. In preliminary experiments, pancreatic beta cells appear hypoplastic with diminished islet insulin immunoreactivity, and no evidence for autoimmune islet involvement. This proposal aims to study the role of mammalian securin in pancreatic beta cell function by assessing insulin transcription, secretion and action, regulation of adipocyte hormones and assessment of pancreatic beta cell development and replication, and pancreatic regeneration. As securin-deficient diabetes is restricted to male mice, intact or gonadectomized PTTG -/- animals will be treated with sex steroids, and their impact on glycemia and pancreatic function assessed. These studies highlight the role of a cell cycle-regulating protein in pancreatic beta cell development and function. In the context of this unique genetic background, these experiments identify securin as a critical factor for pancreatic cell function and provide insights into a novel monogenic cause of diabetes.

描述（由申请人提供）：通过抑制分离蛋白功能，依赖细胞周期的SECERIN蛋白来调节姐妹染色单体分离。我们从大鼠垂体肿瘤细胞中分离出来并表征了垂体转化基因（PTTG），而PTTG在功能上与酵母菌同源。 PTTG在几种肿瘤类型中过表达，并且在某些正常的复制组织（包括睾丸，淋巴细胞）中也过表达。当删除PTTG基因时，产生的基因敲除小鼠是可行的，肥沃的，表现出脾和睾丸发育不全和血小板减少症。令人惊讶的是，六个月后，雄性PTTG - / - 小鼠不会增加体重，患有深度血糖，低血糖，低胰岛素血症和低纤维素血症，具有完整的胰岛素敏感性。在初步实验中，胰腺β细胞显得不适，胰岛素免疫反应性降低，并且没有自身免疫性胰岛受累的证据。该建议旨在通过评估胰岛素转录，分泌和作用，脂肪细胞激素的调节以及评估胰腺β细胞的发育和复制以及胰腺再生来研究哺乳动物证券蛋白在胰腺β细胞功能中的作用。由于缺陷型糖尿病仅限于雄性小鼠，因此将使用性类固醇治疗完整或促性切除型PTTG - / - 动物，并评估了它们对血糖和胰腺功能的影响。这些研究强调了细胞周期调节蛋白在胰腺β细胞发育和功能中的作用。在这种独特的遗传背景的背景下，这些实验将Securin识别为胰腺细胞功能的关键因素，并为新颖的糖尿病单基因原因提供见解。