Pancreatic Islet Neogenesis in Glucose-Infused Rats

葡萄糖输注大鼠的胰岛新生

• 批准号: 6359251
• 负责人: THOMAS JETTON
• 金额: $ 14.63万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6359251
• 关键词: apoptosis; biological models; biological signal transduction; cell growth regulation; cell population study; cell proliferation; confocal scanning microscopy; diabetes mellitus therapy; fluorescence microscopy; gene expression; glucokinase; glucose; histogenesis; hormone regulation /control mechanism; immunocytochemistry; injection /infusion; insulin dependent diabetes mellitus; insulin receptor; laboratory rat; morphometry; pancreatic islet hyperplasia; pancreatic islet transplantation; pancreatic islets; protein kinase; protein structure function; transcription factor

DESCRIPTION: (provided by applicant) Beta cell replacement strategies for the future management of insulin-dependent diabetes will require amplification of pancreatic islet tissue in Vitro for transplantation or induction of new islets by stimulating islet growth within the diabetic patient. Accordingly, a fundamental issue is to identify mechanisms that regulate the development and death of B cells. Towards this end, studies of animal models with experimentally augmented islet mass have generally entailed some form ol pancreatic trauma whereby the identification of the mechanisms involved are confounded by responses to injury. The relative importance of new islet formation from ducts (neogenesis) vs. B cell hyperplasia in existing islets during B\ cell mass expansion in the adult pancreas, as well as the growth factors and signaling pathways that control these two processes, are unknown. The primary goal of this proposal is to investigate islet neogenesis and B hyperplasia in rats undergoing compensatory B cell growth from a glucose infusion (i.e., no direct pancreatic manipulation). We will specifically (1) determine the extent of islet neogenesis vs. B cell growth occurring in glucose-infused rats under hyperglycemic and normoglycemic conditions, (2) investigate the developmental relationships of the cells involved in islet neogenesis based on the expression of key islet transcription factors and B cell functional markers, and (3) analyze the potential role of the insulin signaling cascade during glucose-induced islet neogenesis by examining the cell-specific expression and activation of insulin receptor substrate-2 and protein kinase B/Akt. These studies will establish the foundation for future endeavors to identify and exploit signaling pathways, and the stimulating ligands involved, in order to manipulate islet neogenesis.

描述：（由申请人提供） 胰岛素依赖型糖尿病的未来管理将需要扩大 用于移植或诱导新胰岛的体外胰岛组织 通过刺激糖尿病患者体内的胰岛生长。因此 一个根本问题是确定规范发展的机制， B细胞死亡。为此，动物模型的研究， 实验性增加的胰岛质量通常需要某种形式的 胰腺创伤，其中涉及的机制的鉴定是 对受伤的反应感到困惑。新胰岛的相对重要性 导管形成（新生）与现有胰岛中的B细胞增生 在成年胰腺中B\细胞团扩增期间，以及 控制这两个过程的因子和信号通路是未知的。 本提案的主要目标是研究胰岛新生和B 在经历从葡萄糖的代偿性B细胞生长的大鼠中， 输注（即，没有直接的胰腺操作）。我们将具体（1） 确定胰岛新生与B细胞生长的程度， 高血糖和正常血糖条件下的葡萄糖输注大鼠，（2） 探讨胰岛相关细胞的发育关系 基于关键胰岛转录因子和B表达的新生 细胞功能标志物，和（3）分析胰岛素的潜在作用， 信号级联过程中葡萄糖诱导的胰岛新生，通过检查 胰岛素受体底物-2的细胞特异性表达和活化， 蛋白激酶B/Akt.这些研究将为今后的研究奠定基础。 努力识别和利用信号通路，以及刺激 配体参与，以操纵胰岛新生。