Role of Epac1 in the Pathogenesis of Pulmonary Fibrosis

PROJECT SUMMARY The overall objective of this proposal is to delineate the role of the exchange protein directly activated by cAMP (Epac1) in idiopathic pulmonary fibrosis (IPF) disease. IPF is characterized by progressive scarring and fibrosis of the lungs that results in life-threatening complications such as respiratory failure. Unfortunately, there is no cure for IPF, and our aging world population requires a vast majority of new therapeutic targets and strategies for treating patients with this fatal disease. Most studies in fibrosis focused on increased cAMP to inhibit fibroblast proliferation and differentiation through the PKA pathway, however, neither the regulation of the expression nor the contribution of Epac1 to IPF pathophysiological processes are well defined. Thus, it is interesting to direct the research by specifically regulating the actions of the Epac enzymes independently of PKA in IPF. Recently, the compound AM-001 has been identified and characterized as a novel and potent Epac1 pharmacological inhibitor. AM-001 selectively inhibits Epac1 catalytic activity and displays cardioprotective properties. Such findings reflect the need to assess the key role of Epac1 and its specific inhibitor AM-001 in pulmonary fibrosis (PF) disease. Our preliminary studies show that the expression of Epac1 is significantly increased in lung tissue from IPF patients, IPF diseased fibroblasts, and bleomycin (BLM)-challenged mice compared to controls. Furthermore, Epac1 deficiency mice are protected against BLM induced-lung injury and fibrosis. Furthermore, the knockdown and inhibition of Epac1 by AM-001 attenuate normal and IPF fibroblasts proliferation and the expression of pro-fibrotic markers, TGFβ and interleukin-6 (IL-6). In addition, AM-001 significantly decreases lung fibrosis in vivo in the BLM-induced PF mouse model. RNA sequencing data analyses show key components of the pro-fibrotic genes signature of IPF in AM-001-treated NHLF cells. Based on these data our overall hypothesis is that Epac1 is an important regulator of the fibroblast's pathological state in PF and that Epac1 can serve as a potential therapeutic target by AM-001 for PF disease. In this proposal, we will extend these preliminary findings by testing the following specific aims: Specific Aim 1: To define the expression pattern of Epac1 in humans and mice with PF. Specific Aim 2: To define the mechanisms of Epac1 function in fibroblast activation. Specific Aim 3: To evaluate the effectiveness of a novel Epac1-specific inhibitor AM-001 in a mouse model of pulmonary fibrosis. Collectively, the proposed studies will help increase our understanding of Epac1 role in lung remodeling associated with aged-PF pathogenesis and may lead to the identification of new potential targets to block the progression of this deadly disease.