Despite major advances in the understanding of the pathogenesis of pulmonary fibrosis, many of the therapies that target the most well-studied genes and pathways have not achieved universal success in reversing or even halting disease progression. This, along with the clinical heterogeneity of patients with idiopathic pulmonary fibrosis (IPF), suggest that consideration of other genes in models of disease pathogenesis may be useful. Fibroblasts from patients with IPF differ in the expression of many genes compared to normal fibroblasts, and this laboratory has had a longstanding interest in identifying epigenetic changes that account for these differences. KCNMB1 codes for the beta subunit of the large conductance (BK, Maxi-K, KCa1.1) potassium channel and was identified in our previous microarray study as the top differentially methylated gene in IPF fibroblasts. BK channels modulate potassium current and are well known to be important in vascular tone and smooth muscle biology, but its importance in fibrosis has never been examined. We recently showed in a publication that 1) KCNMB1 expression is increased in fibroblasts from IPF patients, 2) KCNMB1 contributes to increased BK channel activity, and 3) increased function of BK channels promote myofibroblast differentiation, a hallmark of IPF. How it does so and whether this is sufficient to promote or worsen pulmonary fibrosis in vivo is unknown. The objectives of this grant are to determine the mechanism of how BK channels contribute to myofibroblast differentiation and establish the importance of BK channels to animal models of pulmonary fibrosis. Our central hypothesis is that the epigenetic upregulation of KCNMB1 and increased BK channel activity in IPF fibroblasts contribute to pulmonary fibrosis by promoting calcium signaling in fibroblasts, which lead to myofibroblast differentiation.
The First Aim i s to establish the importance of BK channels to the development of pulmonary fibrosis in vivo, and localize its pathogenic actions to lung fibroblasts.
The Second Aim i s to delineate the mechanism by which BK channels contribute to myofibroblast differentiation, with the hypothesis that BK channels promote intracellular calcium signaling, which is necessary for differentiation into myofibroblasts.
The Third Aim i s to determine how expression of KCNMB1 is regulated in lung fibroblasts and how profibrotic stimuli modulates opening and closing of BK channels. This proposal is significant because it establishes BK channels as a novel, but important driver in the pathogenesis of pulmonary fibrosis. Accomplishing these aims will also identify a mechanism and role for BK channels in the differentiation of myofibroblasts that has never been previously described. Ultimately, these studies will serve to identify new targets for future IPF therapeutics.
Idiopathic pulmonary fibrosis is a progressive scarring disease of the lungs with minimally effective therapies. This project is relevant to the overall NIH mission of public health because it identifies a specific potassium ion channel ? the BK channel ? as a novel enabler of myofibroblast activation and ultimately, pulmonary fibrosis. Targeting BK channels would be a new strategy for the treatment of this deadly disease.
