Transforming Growth Factor Beta Superfamily Signaling in Pancreas Biology

胰腺生物学中生长因子β超家族信号转导的转化

• 批准号: 8741613
• 负责人: Sushil Rane
• 金额: $ 33.97万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8741613
• 关键词: Activins; Adult; Beta Cell; Biological Assay; Biology; Cell physiology; Cells; Complex; Development; Diabetes Mellitus; Dominant-Negative Mutation; Exhibits; Functional disorder; Gene Expression; Genes; Genetic Transcription; Glucose; Human; Hyperinsulinism; Hypoglycemia; Inhibin-beta Subunits; Insulin; Insulin Receptor; Islets of Langerhans; Knowledge; Morphogenesis; Mus; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Pancreatic Diseases; Pathogenesis; Pathway interactions; Play; Receptor Signaling; Regulation; Role; Sampling; Signal Pathway; Signal Transduction; Small Interfering RNA; Transforming Growth Factor beta; clinically relevant; established cell line; gene repression; glucose tolerance; improved; in vivo; insulin secretion; islet; mouse model; nonhuman primate; promoter

Transforming Growth Factor-beta/Smad3 Signaling Regulates Insulin Gene Transcription and Pancreatic Islet beta-Cell Function. Pancreatic islet beta-cell dysfunction is a signature feature of Type 2 diabetes pathogenesis. Consequently, knowledge of signals that regulate beta-cell function is of immense clinical relevance. Transforming growth factor (TGF)-beta signaling plays a critical role in pancreatic development although the role of this pathway in the adult pancreas is obscure. We recently defined an important role of the TGF-beta pathway in regulation of insulin gene transcription and beta-cell function. We showed that the TGF-beta signaling effector Smad3 occupies the insulin gene promoter and represses insulin gene transcription. In contrast, Smad3 small interfering RNAs relieve insulin transcriptional repression and enhance insulin levels. Transduction of adenoviral Smad3 into primary human and non-human primate islets suppresses insulin content, whereas, dominant-negative Smad3 enhances insulin levels. Consistent with this, Smad3-deficient mice exhibit moderate hyperinsulinemia and mild hypoglycemia. Moreover, Smad3 deficiency results in improved glucose tolerance and enhanced glucose-stimulated insulin secretion in vivo. In ex vivo perifusion assays, Smad3-deficient islets exhibit improved glucosestimulated insulin release. Interestingly, Smad3-deficient islets harbor an activated insulin-receptor signaling pathway and TGF-beta signaling regulates expression of genes involved in beta-cell function. Together, these studies emphasize TGF-beta/Smad3 signaling as an important regulator of insulin gene transcription and beta-cell function and suggest that components of the TGF-beta signaling pathway may be dysregulated in diabetes. We are examing the beta cell specific role of TGF-beta pathways using mouse models.

转化生长因子-β/Smad 3信号通路调节胰岛素基因转录和胰岛β细胞功能 胰岛β细胞功能障碍是2型糖尿病发病机制的标志性特征。因此，调节β细胞功能的信号的知识具有巨大的临床意义。转化生长因子（TGF）-β信号传导在胰腺发育中起关键作用，尽管该途径在成人胰腺中的作用尚不清楚。我们最近确定了TGF-β通路在调节胰岛素基因转录和β细胞功能中的重要作用。我们发现TGF-β信号效应子Smad 3占据胰岛素基因启动子并抑制胰岛素基因转录。与此相反，Smad 3小干扰RNA解除胰岛素转录抑制，提高胰岛素水平。腺病毒Smad 3转导入原代人和非人灵长类动物胰岛抑制胰岛素含量，而显性负性Smad 3增强胰岛素水平。与此一致，Smad 3缺陷小鼠表现出中度高胰岛素血症和轻度低血糖。此外，Smad 3缺陷导致体内葡萄糖耐量改善和葡萄糖刺激的胰岛素分泌增强。在离体灌注测定中，Smad 3缺陷型胰岛表现出改善的葡萄糖估计胰岛素释放。有趣的是，Smad 3缺陷的胰岛具有激活的胰岛素受体信号传导途径，TGF-β信号传导调节参与β细胞功能的基因的表达。总之，这些研究强调TGF-β/Smad 3信号传导是胰岛素基因转录和β细胞功能的重要调节因子，并表明TGF-β信号传导途径的组分可能在糖尿病中失调。我们正在使用小鼠模型研究TGF-β通路的β细胞特异性作用。