P2 RECEPTORS, EXTRACELLULAR ATP AND ISLET FUNCTION

P2 受体、细胞外 ATP 和胰岛功能

• 批准号: 2889594
• 负责人: THOMAS H STEINBERG
• 金额: $ 17.62万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2889594
• 关键词: adenosine triphosphate; biological signal transduction; calcium channel; calcium flux; cell line; glucose metabolism; human tissue; laboratory mouse; laboratory rabbit; laboratory rat; pancreatic islet function; pancreatic islets; polymerase chain reaction; purinergic receptor; receptor expression

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.

恢复胰岛素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 不明原因。 最近的研究表明，胰岛 细胞表达细胞外ATP的受体，称为P2受体。 这些受体增加细胞内钙，导致细胞内钙离子浓度升高。 ATP的再生分泌，以及随后的钙协调 细胞之间的信号。 因此，刺激钙反应，在一个单一的 细胞导致整个细胞中钙升高的传播 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 这一建议将明确大鼠P2受体的表达和功能 和人胰岛以及几种胰岛素瘤细胞系。而且他们 将检验由P2 Y传播的再生信号 受体调节生理上重要的胰岛素分泌， 是由血糖浓度的变化介导的。 这些 研究将采用各种分子和生物化学技术， 并将使用荧光比率成像来研究钙的反应 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 这条通路是否在决定胰岛素反应中很重要 血糖水平的变化。 因此，这些研究可能 胰岛细胞移植策略的重要意义， 可能为完善胰岛细胞技术提供新的途径， 移植 他们还可以确定新的发展目标， 这些药物在治疗糖尿病中是有用的，因为它们 将阐明细胞外ATP 改变胰岛功能