INTRA CELL COMMUNICATION IN SURGICALLY ALTERED PANCREAS

描述：(改编自调查人员摘要)初步数据 提示脑内存在β细胞内分泌轴 胰岛内生长抑素抑制胰岛素分泌的胰岛。这个 本竞争性更新项目的目的是证明以下几点 假设：1)胰岛内生长抑素通过 人、大鼠和小鼠胰腺的Delta-to-beta细胞内分泌轴和 这种作用是葡萄糖依赖的，2)生长抑素受体亚型 负责抑制胰岛素的是特定物种的，以及3) 基因消融生长抑素受体亚型5将改变胰岛素 小鼠的分泌和葡萄糖的动态平衡。 胰岛内注射生长抑素的效果将通过检查 胰岛素对胰岛内生长抑素免疫中和作用的反应 抗人生长抑素抗体及其Fab片段的研究 分离灌流人、大鼠和小鼠胰腺模型。电子显微镜 将有助于确定免疫中和的间隔。这个 生长抑素受体亚型对胰岛素的抑制作用 通过检测胰岛素分泌对注射阿司匹林的反应来确定 这些模型中的特定生长抑素受体亚型激动剂。 免疫组织化学将使用定向的多克隆抗体进行 对照SSTR 1-5，以确定哪些受体亚型存在于 人、大鼠和小鼠的胰腺。 生长抑素受体亚型5似乎与 抑制小鼠胰岛素分泌，因此将两种模型 使用最先进的转基因技术开发的：第一个是 总生长抑素受体亚型5基因消融模型 一种β细胞特异性生长抑素受体亚型5基因消融模型。 将在这些小鼠身上进行体内和体外生理学研究，以 确定从基因上改变β-三角洲细胞的影响 内分泌轴对胰岛素分泌和血糖稳态的影响。胰腺 将用免疫组织化学方法对基因去除小鼠进行研究 针对生长抑素受体亚型的抗体确定 如果生长抑素受体亚型在基因的胰岛中发生改变 消融的小鼠。 这些研究将有助于阐明调节胰岛素的生理机制。 分泌物，并将决定是否存在物种差异 监管。此外，还将确定是否存在 从基因上改变这些机制的病理生理后果。

DESCRIPTION: (Adapted from investigator's abstract) Preliminary data suggest the presence of the delta-to-beta cell endocrine axis within the islet in which intraislet somatostatin inhibits insulin secretion. The purpose of this competitive renewal project is to prove the following hypotheses: 1) intraislet somatostatin inhibits secretion via a delta-to-beta cell endocrine axis in the human, rat and mouse pancreas and that the effect is glucose-dependent, 2) the somatostatin receptor subtype responsible for the inhibition of insulin is species-specific, and 3) genetic ablation of the somatostatin receptor subtype 5 will alter insulin secretion and glucose homeostasis in the mouse. The effect of intraislet somatostatin will be determined by examining the insulin response to immunoneutralization of intraislet somatostatin with antibodies and FAb fragments of antibodies directed against somatostatin in isolated perfused human, rat and mouse pancreas models. Electron microscopy will help to determine the compartment of immunoneutralization. The somatostatin receptor subtype responsible for the inhibition of insulin will be determined by examining the response of insulin secretion to infusions of specific somatostatin receptor subtype agonists in these models. Immunohistochemistry will be performed using polyclonal antibodies directed against SSTR 1-5 to determine which receptor subtypes are present in the human, rat and mouse pancreas. It appears that the somatostatin receptor subtype 5 is responsible for inhibition of mouse insulin secretion, therefore two models will be developed using state-of-the-art transgenic techniques: the first is a total somatostatin receptor subtype 5 gene ablation model and the second is a beta cell-specific somatostatin receptor subtype 5 gene ablation model. In vivo and in vitro physiology studies will be performed in these mice to determine the effect of genetically altering the delta-to-beta cell endocrine axis on insulin secretion and glucose homeostasis. The pancreas of the gene-ablated mice will be studied using immunohistochemistry with antibodies directed against the somatostatin receptor subtypes to determine if the somatostatin receptor subtypes are altered in the islets of the gene ablated mice. These studies will help elucidate physiologic mechanisms regulating insulin secretion and will determine whether there are species differences in this regulation. Furthermore, it will be determined whether there are pathophysiologic consequences to genetically altering these mechanisms.