Pancreatic Islet Neogenesis in Glucose-Infused Rats

描述：(申请人提供)未来治疗胰岛素依赖型糖尿病的Beta细胞替代策略将需要放大 体外胰岛组织用于移植或诱导新的胰岛 通过刺激糖尿病患者体内的胰岛生长。因此，a 根本问题是确定规范发展和发展的机制 B细胞死亡。为此，对动物模型的研究 实验上增大的胰岛质量通常会导致某种形式的OOL 胰腺创伤所涉及的机制的识别是 对受伤的反应感到困惑。新小岛的相对重要性 现有胰岛的导管形成(新生)与B细胞增殖 在成人胰腺的B细胞团扩增以及生长过程中 控制这两个过程的因素和信号通路尚不清楚。 这项建议的主要目标是研究胰岛新生和B细胞 大鼠葡萄糖代偿生长过程中B细胞的增殖 输液(即不进行直接的胰腺操作)。我们将具体(1) 确定胰岛新生程度与B细胞生长之间的关系 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蛋白表达的新生 细胞功能标志物，以及(3)分析胰岛素的潜在作用 通过检测葡萄糖诱导的胰岛新生过程中的信号级联 胰岛素受体底物-2和胰岛素受体底物-2的细胞特异性表达和激活 蛋白激酶B/Akt.这些研究将为今后的工作奠定基础 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。

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.