? ? Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and usually fatal lung disease of unknown etiology, characterized by alveolar type II epithelial cell hyperplasia, fibroblast accumulation, excessive extracellular matrix deposition, and destruction of the normal lung architecture. Long-term survival of IPF patients is poor, with a 5-year survival rate of only 20%. Historically, anti-inflammatory agents have been the mainstay of therapy, but have been proven to be ineffective in reducing either the severity or progression of the disease. This demands a better understanding of the molecular mechanisms underlying the pathogenesis and progression of this disease. Hence the identification of novel signal molecules or pathways involved in the pathogenesis of IPF offers high potential to provide new targets for therapeutic intervention in IPF. In this proposal, we seek to determine whether the newly described serine/threonine protein kinase D (PKD) family kinases are involved in the pathogenesis and progression of IPF. PKD family kinases include three isoforms, PKD1, PKD2 and PKD3. PKD1 is the best characterized isoform of this family so far and has been implicated in the histone deacetylase-dependent gene expression, cell migration, survival/apoptosis, and membrane trafficking. By studying PKDs in endothelial cells, we showed for the first time that PKD2 played a critical role in endothelial cell proliferation and migration by modulating the expression of key growth factor receptors involved in angiogenesis. In contrast to PKD2 and PKD3, we found that PKD1 was critical for agonist-induced cytokine production in endothelial cells. Interestingly, we found that PKD1 and PKD2 were strongly expressed in lung tissues. Moreover, PKD1 was predominantly expressed in normal human lung fibroblasts, while PKD2 was preferably expressed in human lung alveolar epithelial cells and lung vascular endothelial cells. These data suggest that PKD1 and PKD2 may also play roles in the regulation of cell proliferation, migration, apoptosis, or cytokine production in alveolar epithelial cells and lung fibroblasts. On the basis of these novel findings, we hypothesize that alteration in the expression and activities/activation of PKD family kinases may correlate with the development, progression and severity of IPF.
The Specific Aims of this proposal are:
Aim 1) To correlate the expression and activities/activation of PKD family kinases (PKD1, PKD2 and PKD3) with the presence and/or disease severity of IPF;
Aim 2) To identify the specific cell types involved in the expression or activation of PKD1, PKD2 or PKD3 in lung tissues of patients with various phases of IPF. We anticipate that this proposal will provide valuable information to establish proof-of concept in humans that alteration in the expression or activities/activation of PKD family kinases is involved in the pathogenesis and progression of IPF, which may provide a novel approach to therapeutic intervention in IPF. (End of Abstract) ? ?
? ? This proposal is designed to test the hypothesis that the newly described serine/threonine PKD family kinases are involved in the pathogenesis and progression of Idiopathic pulmonary fibrosis by conducting research in lung tissues of patients with various phases of pulmonary fibrosis obtained from the Lung Tissue Research Consortium. ? ? ? ?
| Gan, Huachen; McKenzie, Raymond; Hao, Qin et al. (2014) Protein kinase D is increased and activated in lung epithelial cells and macrophages in idiopathic pulmonary fibrosis. PLoS One 9:e101983 |
