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.

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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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Molecular and Integrative Signal Transduction Study Section (MIST)
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Dunsmore, Sarah
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University of Texas Health Science Center Houston
Schools of Medicine
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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
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
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
Banerjee, Upasana; Cheng, Xiaodong (2015) Exchange protein directly activated by cAMP encoded by the mammalian rapgef3 gene: Structure, function and therapeutics. Gene 570:157-67
Almahariq, Muayad; Chao, Celia; Mei, Fang C et al. (2015) Pharmacological inhibition and genetic knockdown of exchange protein directly activated by cAMP 1 reduce pancreatic cancer metastasis in vivo. Mol Pharmacol 87:142-9
Almahariq, Muayad; Mei, Fang C; Wang, Hui et al. (2015) Exchange protein directly activated by cAMP modulates regulatory T-cell-mediated immunosuppression. Biochem J 465:295-303
Zhu, Yingmin; Chen, Haijun; Boulton, Stephen et al. (2015) Biochemical and pharmacological characterizations of ESI-09 based EPAC inhibitors: defining the ESI-09 "therapeutic window". Sci Rep 5:9344
Ye, Na; Zhu, Yingmin; Chen, Haijun et al. (2015) Structure-Activity Relationship Studies of Substituted 2-(Isoxazol-3-yl)-2-oxo-N'-phenyl-acetohydrazonoyl Cyanide Analogues: Identification of Potent Exchange Proteins Directly Activated by cAMP (EPAC) Antagonists. J Med Chem 58:6033-47
Schwede, Frank; Chepurny, Oleg G; Kaufholz, Melanie et al. (2015) Rp-cAMPS Prodrugs Reveal the cAMP Dependence of First-Phase Glucose-Stimulated Insulin Secretion. Mol Endocrinol 29:988-1005
Almahariq, Muayad; Mei, Fang C; Cheng, Xiaodong (2014) Cyclic AMP sensor EPAC proteins and energy homeostasis. Trends Endocrinol Metab 25:60-71

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