P2 RECEPTORS, EXTRACELLULAR ATP AND ISLET FUNCTION

胰岛素的恢复是治疗胰岛素的关键- 依赖型糖尿病。胰岛细胞移植 是一种胰岛素替代策略，但对 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。 这些受体增加了细胞内的钙，从而导致 三磷酸腺苷的再生分泌和随后的钙的协调 细胞间的信号。从而在单个细胞中刺激钙反应 细胞导致整个细胞内钙升高的繁殖 人口。这些钙信号对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 提案将确定P2受体在大鼠体内的表达和功能 和人类胰岛以及几个胰岛素瘤细胞系。此外，他们还 将检验这样一种假设，即由P2Y传播的再生信号 受体调节生理上重要的胰岛素分泌， 是通过血糖浓度的变化来调节的。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 在这些牢房里。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 这一途径在确定胰岛素反应中是否重要 血糖水平的变化。因此，这些研究可能会 胰岛细胞移植策略的重要意义，以及 可能为完善胰岛细胞的技术提供新的途径 移植。他们还可能为开发确定新的目标 可能对治疗糖尿病有用的药物，因为它们 将阐明细胞外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.