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，目前的药物治疗靶向cAMP信号通路多于任何其他通路并不奇怪。在多细胞真核生物中，cAMP的作用主要通过两种广泛表达的胞内cAMP受体来转导，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直接激活的交换蛋白（Epac/cAMP-GEF）。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日益受到重视。迄今为止，大多数Epac蛋白的功能分析已在体外环境下进行。为了弥补这一差距，我们将审问生物 使用组织特异性Epac 1敲除小鼠模型，研究Epac 1在生理环境中的功能，并使用新型Epac特异性抑制剂测试Epac 1作为治疗靶点的潜力。这项研究是基于我们实验室对Epac介导的信号传导进行的十多年的广泛研究，并直接建立在实验室最近的几项新进展的基础上，包括全球Epac 1基因敲除小鼠的表征和一流Epac特异性抑制剂的发现。新的遗传动物模型和小分子探针的结合将使我们能够揭示Epac 1的体内功能，开发新的药理学工具来研究Epac介导的细胞信号传导和疾病机制，这可能最终导致新的基于机制的治疗策略，用于瘦素抵抗/肥胖。

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.