Epac/cAMP-GEF, A Novel Intracellular cAMP Receptor

描述（由申请人提供）：原型第二信使环AMP （cAMP）在生理和病理条件下调节无数重要的生物过程，包括癌症，糖尿病，心力衰竭，炎症和神经系统疾病。因此，目前的药物靶向cAMP信号通路比其他任何途径都要多，这并不奇怪。在多细胞真核生物中，cAMP的作用主要由两种普遍表达的细胞内cAMP受体转导，即经典的蛋白激酶A/cAMP依赖性蛋白激酶（PKA/cAPK）和最近发现的由cAMP/cAMP调节的鸟嘌呤核苷酸交换因子（Epac/cAMP- gef）直接激活的交换蛋白。Epac蛋白作为cAMP的主要细胞内受体，在正常生理功能和疾病中的重要作用越来越受到重视。迄今为止，大多数Epac蛋白的功能分析都是在体外环境下进行的。为了弥补这个差距，我们将询问生物

DESCRIPTION (provided by applicant): The prototypic second messenger cyclic AMP (cAMP) regulates a myriad of important biological processes under both physiological and pathological conditions, including cancer, diabetes, heart failure, inflammation and neurological disorders. Hence, it is not surprising that current pharmaceutical medications target the cAMP signaling pathway more than any other pathway. In multi-cellular eukaryotic organisms, the effects of cAMP are mainly transduced by two ubiquitously-expressed intracellular cAMP receptors, the classic protein kinase A/cAMP-dependent protein kinase (PKA/cAPK) and the more recently discovered exchange proteins directly activated by cAMP/cAMP-regulated guanine nucleotide exchange factor (Epac/cAMP-GEF). As a major intracellular receptor of cAMP, the important roles that Epac proteins play in normal physiological functions and diseases are now increasingly appreciated. To date, most functional analyses of Epac proteins have been performed under in vitro settings. To bridge this gap, we will interrogate the biological functions of Epac1 in physiological setting using tissue-specific Epac1 knockout mouse models and test the potential of Epac1 as a therapeutic target using novel Epac specific inhibitors. The proposed research is based on more than a decade of extensive studies of the Epac-mediated signaling performed in our laboratory and directly builds on a several recent novel developments in the lab including the characterization of global Epac1 null mice and the discovery of first-in-class Epac specific inhibitors. The combination of new genetic animal models and small molecule probes will enable us to reveal much desired in vivo functions of Epac1, to develop new pharmacological tools for investigating Epac-mediated cell signaling and disease mechanisms, which may eventually lead to novel mechanism-based therapeutic strategies for leptin resistance/obesity.