P2 RECEPTORS, EXTRACELLULAR ATP AND ISLET FUNCTION

胰岛素的恢复对于胰岛素治疗至关重要 依赖性糖尿病。 胰岛细胞移植 是一种胰岛素替代策略，但效果不佳 原因不明。 最近的研究表明，胰岛 细胞表达细胞外 ATP 受体，称为 P2 受体。 这些受体增加细胞内钙，从而导致 ATP 的再生分泌，以及随后的钙协调 细胞间的信号。 因此刺激钙反应在一个单一的 细胞导致整个细胞内钙浓度升高 人口。这些钙信号对于适当的胰岛素至关重要 分泌，并可能用于调节细胞死亡。 这方面的研究 该提案将定义大鼠 P2 受体的表达和功能 和人类胰岛以及几种胰岛素瘤细胞系中。此外，他们 将检验 P2Y 传播再生信号的假设 受体调节生理上重要的胰岛素分泌 由血糖浓度的变化介导。 这些 研究将采用各种分子和生化技术， 还将使用荧光比率成像来研究钙反应 在这些细胞中。 通过了解细胞外 ATP 和 P2受体改变胰岛素分泌，这些研究将确定 该途径对于确定胰岛素反应是否重要 血糖水平的变化。 因此，这些研究可能具有 对胰岛细胞移植策略的重要影响，以及 可能为改进胰岛细胞技术提供新方法 移植。 他们还可能确定新的发展目标 可用于治疗糖尿病的药物，因为它们 将揭示细胞外 ATP 的基本机制 改变胰岛功能。

Restoration of insulin is critical for the treatment of insulin- dependent diabetes mellitus. Transplantation of pancreatic islet cells is a strategy for insulin replacement which has not worked well for unclear reasons. Recent work has demonstrated that pancreatic islet cells express receptors for extracellular ATP, termed P2 receptors. These receptors increase intracellular calcium which leads to a regenerative secretion of ATP, and subsequent coordination of calcium signals among cells. Thus stimulation of a calcium response in a single cell results in the propagation of a calcium rise in the whole cell population. These calcium signals are critical for proper insulin secretion, and possibly for regulating cell death. The studies in this proposal will define the expression and function of P2 receptors in rat and human islets and in several insulinoma cell lines. Furthermore, they will test the hypothesis that the regenerative signal propagated by P2Y receptors modulates the physiologically-important insulin secretion that is mediated by changes in the blood glucose concentration. These studies will employ a variety of molecular and biochemical techniques, and will also use fluorescence ratio imaging to study calcium responses in these cells. By understanding the way in which extracellular ATP and P2 receptors alter insulin secretion, these studies will determine whether this pathway is important in determining the insulin response to changes in the blood sugar level. These studies may therefore have important implications for islet cell transplantation strategies, and may offer new approaches to refining the techniques of islet cell transplantation. They may also identify new targets for the development of agents that would be useful in the treatment of diabetes because they will shed light on the basic mechanisms by which extracellular ATP alters islet function.