Physiological and functional effects of beta-cell-specific inactivation of the PGE2 receptor EP3

项目摘要/摘要 在美国，2型糖尿病是一个主要的健康问题。当个人未能补偿时，就会发生这种情况 因为胰腺β细胞对胰岛素的需求增加。前列腺素E受体EP3(由 对前列腺素E2(PGE2)有反应的Ptger3)已被证明能抑制胰岛素的分泌。EP3是 糖尿病患者随着年龄的增长而上调。我们实验室的数据表明，体外实验 药物抑制EP3可增加β细胞质量和存活率。EP3在β细胞中的特异性作用 还没有经过检查。我建议使用β细胞特异性EP3KO小鼠模型来确定EP3的作用 在高脂肪饮食背景下的失活。此外，FOXM1是β细胞所必需的转录因子 扩散。FOXM1水平随年龄增长而降低，EP3水平随年龄增长而升高。在这份提案中，我概述了实验 为了阐明FOXM1在调节Ptger3表达方面的作用(如果有的话)。

Project summary/Abstract Type 2 diabetes is a major health concern in the United States. It occurs when individuals fail to compensate for an increased demand for insulin from the pancreatic β cells. The prostaglandin E receptor EP3 (encoded by Ptger3), which responds to prostaglandin E2 (PGE2), has been shown to inhibit insulin secretion. EP3 is upregulated in diabetic individuals and with age. Data from our lab has demonstrated that ex vivo pharmacological inhibition of EP3 increases β cell mass and survival. The role of EP3 specifically in the β cell has not been examined. I propose using a β-cell-specific EP3 KO mouse model to determine the effect of EP3 inactivation in the context of high fat diet. In addition, FoxM1 is a transcription factor necessary for β cell proliferation. FoxM1 levels decrease with age while EP3 levels increase. In this proposal, I outline experiments to elucidate what role, if any, FoxM1 has in regulating Ptger3 expression.