PKD Family Kinase Function and Signaling in Lung Fibroblasts

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DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and usually fatal lung disease of unknown etiology, characterized by lung fibroblast activation and proliferation, excessive deposition of extracellular matrix (ECM), 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. Hence, there is a profound need for the identification of novel drugable targets to develop efficacious new therapies for treating IPF patients. Because lung fibroblasts are primary effector cells in IPF, the identification of novel drugable molecules or pathways that control IPF lung fibroblast biology may lead to more specific and efficacious therapeutic intervention in IPF. In this proposal, we seek to determine whether the serine/threonine protein kinase D (PKD) family kinases play critical roles in IPF fibroblast activation, production of ECM, and expression of profibrotic growth factor receptors. PKD family kinases include PKD1, PKD2 and PKD3. Herein, we found for the first time that all the PKD isoforms were readily detected in fibroblastic foci, the hallmark lesions of IPF. We further showed that PKD1 and PKD2 were constitutively activated in primary IPF fibroblasts but not in control normal human lung fibroblasts. Moreover, PKD1 and PKD2 could be further activated by profibrotic growth factors in primary IPF fibroblasts. Interestingly, PKD inhibition markedly downregulated the protein levels of procollagen and fibronectin without significantly affecting their mRNA levels in IPF fibroblasts. Whereas, PKD inhibition markedly suppressed both mRNA and protein levels of profibrotic platelet-derived growth factor receptor-( (PDGFR() in the fibroblasts. On the basis of these novel findings, this resubmission R21 proposal is designed to test the hypothesis that PKD family kinases may play critical roles in IPF fibroblast biology, including the fibroblast activation, ECM production and expression of profibrotic growth factor receptors, which may offer novel drugable targets for halting IPF progression. The Specific Aims of this resubmission proposal are: Aim 1) To characterize the constitutive and profibrotic agonist-induced activation of PKD family kinases in primary IPF fibroblasts; Aim 2) To determine the roles of PKD family kinases and the mechanisms in the production of profibrotic matrix in primary IPF fibroblasts; Aim 3) To determine the roles of PKD family kinases and the mechanisms in IPF fibroblast expression of profibrotic PDGF receptor-(. We anticipate that this proposal will identify PKD family kinases as novel and important modulators of lung fibroblast biology involved in the pathogenesis and progression of IPF, therefore targeting to inhibit PKD family kinases or a specific PKD isoform may provide a novel and efficacious therapeutic intervention for IPF patients. PUBLIC HEALTH RELEVANCE: This resubmission R21 proposal is designed to test the hypothesis that PKD family kinases may play critical roles in lung fibroblast biology, including the fibroblast activation, production of extracellular matrix, and expression of profibrotic growth factor receptors, which may offer novel drugable targets for halting the progression of idiopathic pulmonary fibrosis.