Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disorder with no effective medical treatment. IPF is characterized by fibroblastic/myofibroblastic foci and excessive extracellular matrix protein accumulation, in which fibroblast migration into the injured areas and myofibroblast differentiation play critical roles. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is required for cell migration and myofibroblast differentiation. FAK-mediated signaling is limited by an FAK's C-terminal homologous protein, known as FAK-related non-kinase (FRNK), whose action that our data suggest to be central to pulmonary fibrogenesis. FRNK is downregulated in human IPF fibrotic lesions and the extent of its downregulation tightly correlates with migration rate in IPF lung fibroblasts. In an experimental murine model of pulmonary fibrosis, gain (and loss) of FRNK approaches demonstrates that FRNK functions as an endogenous brake on the resultant fibrosis through multiple mechanisms. Based upon these studies, we hypothesize that FRNK acts as a negative regulator of lung fibrosis through inhibition of myofibroblast differentiation ad fibroblast motility, and that pathologically rapid decay of FRNK mRNA underlies the increased pro-fibrotic effect(s) of TGF-?1 in IPF lung fibroblasts. To test the hypothesis, three specific ais are proposed.
In Aim 1, we will determine the intracellular signaling pathway by which impaired FRNK function promotes myofibroblast differentiation, and examine the effect of gain of FRNK in vivo, specifically in myofibroblasts, on fibrogenesis. Increased S100A4 expression is associated with increased lung fibrosis in FRNK deficient mice.
In Aim 2, we will examine the functional role of S100A4 in fibroblast migration and the mechanism whereby FRNK/FAK axis mediates in vivo fibrogenesis in S100A4-expressing cells.
In Aim 3, we will determine the molecular mechanism of pathologic FRNK downregulation in IPF fibroblasts, and its attendant functional downstream consequences. These studies will support our long-term goal to utilize knowledge gained from these studies to develop novel therapeutic approaches targeted to IPF in humans.
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease. Currently there is no effective therapy available to limit the progression o fibrosis for IPF patients. The knowledge gained in these studies can help us to achieve our long-term goal to develop novel therapy to limit lung fibrosis in IPF patients.
|Ahluwalia, Manmeet S; Bou-Anak, Stephanie; Burgett, Monica E et al. (2017) Correlation of higher levels of soluble TNF-R1 with a shorter survival, independent of age, in recurrent glioblastoma. J Neurooncol 131:449-458|
|Zhao, Xue-Ke; Yu, Lei; Cheng, Ming-Liang et al. (2017) Focal Adhesion Kinase Regulates Hepatic Stellate Cell Activation and Liver Fibrosis. Sci Rep 7:4032|
|Zhao, Xue-Ke; Che, Pulin; Cheng, Ming-Liang et al. (2016) Tristetraprolin Down-Regulation Contributes to Persistent TNF-Alpha Expression Induced by Cigarette Smoke Extract through a Post-Transcriptional Mechanism. PLoS One 11:e0167451|
|Wagener, Brant M; Hu, Meng; Zheng, Anni et al. (2016) Neuronal Wiskott-Aldrich syndrome protein regulates TGF-?1-mediated lung vascular permeability. FASEB J 30:2557-69|
|Rangarajan, Sunad; Kurundkar, Ashish; Kurundkar, Deepali et al. (2016) Novel Mechanisms for the Antifibrotic Action of Nintedanib. Am J Respir Cell Mol Biol 54:51-9|
|Scheraga, Rachel G; Abraham, Susamma; Niese, Kathryn A et al. (2016) TRPV4 Mechanosensitive Ion Channel Regulates Lipopolysaccharide-Stimulated Macrophage Phagocytosis. J Immunol 196:428-36|
|Southern, Brian D; Grove, Lisa M; Rahaman, Shaik O et al. (2016) Matrix-driven Myosin II Mediates the Pro-fibrotic Fibroblast Phenotype. J Biol Chem 291:6083-95|
|Huang, Wen-Tan; Akhter, Hasina; Jiang, Chunsun et al. (2015) Plasminogen activator inhibitor 1, fibroblast apoptosis resistance, and aging-related susceptibility to lung fibrosis. Exp Gerontol 61:62-75|
|Zhou, Yong; Chen, Huaping; Ambalavanan, Namasivayam et al. (2015) Noninvasive imaging of experimental lung fibrosis. Am J Respir Cell Mol Biol 53:8-13|
|Che, Pulin; Yang, Youfeng; Han, Xiaosi et al. (2015) S100A4 promotes pancreatic cancer progression through a dual signaling pathway mediated by Src and focal adhesion kinase. Sci Rep 5:8453|
Showing the most recent 10 out of 28 publications