A2aR/Egr-1/Pdx-1信号介导咖啡因所致的胎胰腺发育异常

糖尿病的发育起源与胎胰腺发育异常有关，后者表现为β细胞数量不足和功能低下。我们前期发现，孕期咖啡因暴露所致宫内生长迟缓胎鼠胰腺发育异常可延续至成年，引起糖耐量减低和糖尿病易感，但机制不明。文献提示，胰腺发育分化和功能主控基因Pdx-1表达受早期生长反应因子-1（Egr-1）正向调节，后者可招募组蛋白乙酰化酶影响靶基因表遗传修饰并且自身受cAMP/PKA通路调控。咖啡因可通过拮抗腺苷受体2a（A2aR），抑制cAMP/PKA通路。预实验发现，咖啡因可致胎鼠胰腺A2aR、Egr-1和Pdx-1表达降低。推测：咖啡因可抑制A2aR/cAMP/PKA/Egr-1信号，引起Pdx-1组蛋白乙酰化及表达降低，导致胎胰腺发育异常。本项目拟从整体和细胞水平，阐明A2aR/Egr-1/Pdx-1信号介导咖啡因所致胎胰腺发育异常的表遗传调控机制，为认识咖啡因发育毒性和寻找胎源性糖尿病早期防治策略提供相关依据。

Developmental origin of diabetes is associated with impaired fetal pancreatic development which is characterized by insufficient mass and malfunction of β cells. We have previously found that prenatal caffeine exposure induced impaired pancreatic development in intrauterine growth retarded fetal rats, which could be persisted to adulthood and caused glucose intolerance and increased susceptibility to diabetes, but the mechanism remained unknown. As a master regulator of differentiation and function during fetal pancreatic development, pancreatic and duodenal homeobox 1 (Pdx-1) is positively regulated by early growth response 1 (Egr-1). Meanwhile, Egr-1 can recruit histone acetyltransferase to epigenetically regulate target genes while it is also modulated by upstream cAMP/PKA signaling. Caffeine could inhibit cAMP/PKA signaling by antagonizing adenosine receptor 2a (A2aR). The preliminary experimental results showed that prenatal caffeine exposure decreased the mRNA expressions of pancreatic A2aR Egr-1 and Pdx-1. Basing on the above, we hypothesize that caffeine may suppress A2aR/cAMP/PKA/Egr-1 signaling, which results in lowered histone acetylation and decreased expressions of Pdx-1 and finally impairs fetal pancreatic development. The aim of the present project is to demonstrate the epigenetic mechanism of A2aR/Egr-1/Pdx-1 signaling mediated impaired fetal pancreatic development induced by caffeine in vivo and in vitro. This project would provide theoretical and experimental basis for addressing developmental toxicity of caffeine and exploring the early prevention strategy of fetal originated diabetes.