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.
|Almahariq, Muayad; Mei, Fang C; Cheng, Xiaodong (2014) Cyclic AMP sensor EPAC proteins and energy homeostasis. Trends Endocrinol Metab 25:60-71|
|Tao, Xinrong; Mei, Feng; Agrawal, Anurodh et al. (2014) Blocking of exchange proteins directly activated by cAMP leads to reduced replication of Middle East respiratory syndrome coronavirus. J Virol 88:3902-10|
|Chen, Haijun; Wild, Christopher; Zhou, Xiaobin et al. (2014) Recent advances in the discovery of small molecules targeting exchange proteins directly activated by cAMP (EPAC). J Med Chem 57:3651-65|
|Chen, Haijun; Ding, Chunyong; Wild, Christopher et al. (2013) Efficient Synthesis of ESI-09, A Novel Non-cyclic Nucleotide EPAC Antagonist. Tetrahedron Lett 54:1546-1549|
|Almahariq, Muayad; Tsalkova, Tamara; Mei, Fang C et al. (2013) A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion. Mol Pharmacol 83:122-8|
|Yan, Jingbo; Mei, Fang C; Cheng, Hongqiang et al. (2013) Enhanced leptin sensitivity, reduced adiposity, and improved glucose homeostasis in mice lacking exchange protein directly activated by cyclic AMP isoform 1. Mol Cell Biol 33:918-26|
|Chepurny, Oleg G; Bertinetti, Daniela; Diskar, Mandy et al. (2013) Stimulation of proglucagon gene expression by human GPR119 in enteroendocrine L-cell line GLUTag. Mol Endocrinol 27:1267-82|
|Chen, Haijun; Tsalkova, Tamara; Chepurny, Oleg G et al. (2013) Identification and characterization of small molecules as potent and specific EPAC2 antagonists. J Med Chem 56:952-62|
|Zhang, Adrianna P P; Bornholdt, Zachary A; Liu, Tong et al. (2012) The ebola virus interferon antagonist VP24 directly binds STAT1 and has a novel, pyramidal fold. PLoS Pathog 8:e1002550|
|Lu, Weiya D; Liu, Tong; Li, Sheng et al. (2012) The prohormone proenkephalin possesses differential conformational features of subdomains revealed by rapid H-D exchange mass spectrometry. Protein Sci 21:178-87|
Showing the most recent 10 out of 49 publications