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

项目概要/摘要 2型糖尿病在美国是一个主要的健康问题。它发生在个人无法补偿 胰腺β细胞对胰岛素的需求增加。前列腺素E受体EP 3（由 对前列腺素E2（PGE 2）有反应的Ptger 3）已被证明能抑制胰岛素分泌。EP 3是 在糖尿病个体中随着年龄的增长而上调。我们实验室的数据表明， EP 3的药理学抑制增加β细胞质量和存活。EP 3在β细胞中的作用 还没有被检查。我建议使用β细胞特异性EP 3 KO小鼠模型来确定EP 3的作用。 在高脂肪饮食的情况下失活。此外，FoxM 1是β细胞所必需的转录因子， 增殖FoxM 1水平随着年龄的增长而下降，而EP 3水平则随着年龄的增长而增加。在这个建议中，我概述了实验 阐明FoxM 1在调节Ptger 3表达中的作用。

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.