Idiopathic Pulmonary fibrosis (IPF) is a deadly disease with no effective treatments. The disease is characterized by the appearance of fibroblastic foci in the lungs and an excess of TGF-? that drives the differentiation of fibroblasts to myofibroblasts. These myofibroblasts are the major effector cell type in fibrosis producing excess amounts of the extracellular matrix proteins including collagen and fibronectin. Myofibroblast also up-regulate the contractile protein alpha-smooth muscle actin and a potentially pro- fibrotic protein, tissue transglutaminase 2 (TG2). TG2 has multiple potential pro-fibrotic functions including the enzymatic cross linking of proteins and contributes to cell adhesion and migration. Recently, TG2 was shown to control the function of the transcription factor peroxisome proliferator activated receptor gamma (PPAR?). PPAR? is a nuclear hormone receptor involved in adipogenesis and insulin sensitization that has recently been implicated in the control of myofibroblast differentiation. In vitro studies using PPAR? agonists have shown that PPAR? activation is able to block TGF-? driven differentiation of myofibroblasts. Dysregulation of this PPAR? function, could result in uninhibited TGF-? driven fibroblast to myofibroblast transdifferentiation. The central hypothesis to be tested in this application is that there is dysregulation of PPAR? in IPF leading to increased TGF-? mediated myofibroblast differentiation, increased extracellular matrix production, and increased TG2 levels. The increase in TG2 then further downregulates PPAR? leading to a vicious feedback loop.
In Aim 1, the levels of PPAR? and TG2 protein and mRNA in human IPF lung samples and bronchoalveolar lavage fluid will be examined. In vitro studies will be completed using primary human lung fibroblasts to study the reciprocal control of PPAR? and TG2.
In Aim 2, the ability of PPAR? ligands to block TGF-? induced pulmonary fibrosis will be tested in a pre-clinical mouse model. This in vivo model will also be used to examine the role of TG2 in the development of pulmonary fibrosis by utilizing a TG2 knockout mouse. The knowledge gained from these studies will improve our understanding of the pathogenesis of IPF and help identify novel therapeutic targets. The pathogenesis of pulmonary fibrosis is incompletely understood and no effective clinical therapies exist for this debilitating disease. This application seeks to improve the understanding of the disease and to identify possible therapeutic targets.
|Olsen, Keith C; Epa, Amali P; Kulkarni, Ajit A et al. (2014) Inhibition of transglutaminase 2, a novel target for pulmonary fibrosis, by two small electrophilic molecules. Am J Respir Cell Mol Biol 50:737-47|
|Kulkarni, Ajit A; Thatcher, Thomas H; Olsen, Keith C et al. (2011) PPAR-? ligands repress TGF?-induced myofibroblast differentiation by targeting the PI3K/Akt pathway: implications for therapy of fibrosis. PLoS One 6:e15909|
|Olsen, Keith C; Sapinoro, Ramil E; Kottmann, R M et al. (2011) Transglutaminase 2 and its role in pulmonary fibrosis. Am J Respir Crit Care Med 184:699-707|