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.
Our study focuses on applying genetic and pharmacological approaches to unveil the physiological functions of an important signaling protein that has been implicated in many human diseases including obesity and diabetes. These studies may lead to new insight into understanding disease mechanisms and novel mechanism-based therapeutic strategies.
|Yang, Wenli; Mei, Fang C; Cheng, Xiaodong (2018) EPAC1 regulates endothelial annexin A2 cell surface translocation and plasminogen activation. FASEB J 32:2212-2222|
|Robichaux 3rd, William G; Cheng, Xiaodong (2018) Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development. Physiol Rev 98:919-1053|
|Zhu, Yingmin; Mei, Fang; Luo, Pei et al. (2017) A cell-based, quantitative and isoform-specific assay for exchange proteins directly activated by cAMP. Sci Rep 7:6200|
|Wang, Pingyuan; Liu, Zhiqing; Chen, Haiying et al. (2017) Exchange proteins directly activated by cAMP (EPACs): Emerging therapeutic targets. Bioorg Med Chem Lett 27:1633-1639|
|Liu, Zhiqing; Zhu, Yingmin; Chen, Haiying et al. (2017) Structure-activity relationships of 2-substituted phenyl-N-phenyl-2-oxoacetohydrazonoyl cyanides as novel antagonists of exchange proteins directly activated by cAMP (EPACs). Bioorg Med Chem Lett 27:5163-5166|
|Ye, Na; Zhu, Yingmin; Liu, Zhiqing et al. (2017) Identification of novel 2-(benzo[d]isoxazol-3-yl)-2-oxo-N-phenylacetohydrazonoyl cyanide analoguesas potent EPAC antagonists. Eur J Med Chem 134:62-71|
|Almahariq, Muayad; Mei, Fang C; Cheng, Xiaodong (2016) The pleiotropic role of exchange protein directly activated by cAMP 1 (EPAC1) in cancer: implications for therapeutic intervention. Acta Biochim Biophys Sin (Shanghai) 48:75-81|
|Hu, Yaohua; Robichaux 3rd, William G; Mei, Fang C et al. (2016) Role of Exchange Protein Directly Activated by Cyclic AMP Isoform 1 in Energy Homeostasis: Regulation of Leptin Expression and Secretion in White Adipose Tissue. Mol Cell Biol 36:2440-50|
|Wang, Hui; Robichaux, William G; Wang, Ziqing et al. (2016) Inhibition of Epac1 suppresses mitochondrial fission and reduces neointima formation induced by vascular injury. Sci Rep 6:36552|
|Singhmar, Pooja; Huo, XiaoJiao; Eijkelkamp, Niels et al. (2016) Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1. Proc Natl Acad Sci U S A 113:3036-41|
Showing the most recent 10 out of 73 publications