Idiopathic pulmonary fibrosis (IPF) is characterized by unrelenting scarring and stiffening of the lungs that leads to death within 3-4 years after diagnosis. New treatments are needed to abrupt the progression of this disease. We have found that the focal adhesion gene, tensin (TNS1), is induced by the pro-fibrotic transcription factors, MKL1/SRF, and plays a role in the formation of fibronectin matrix. A single nucleotide polymorphism in the TNS1 gene ( is associated with lung function decline from all causes. It is not known how TNS1 mediates matrix remodeling and lung function decline. We hypothesize that TNS1 may be critical in the formation of extracellular matrix in the lung in response to tissue injury. To test this hypothesis, we will: rs2571445, W1197R) Aim 1. Determine the role of TNS1 in mediating cell-matrix interactions. In this aim, we will perform a series of loss and gain of function investigations in human lung fibroblasts to determine how normal and polymorphic TNS1 affects fibrillar adhesion formation and ECM deposition.
Aim 2. Determine the role of TNS1 in modifying the development of pulmonary fibrosis. In this aim, we will create mice that allow for Cre recombinase mediating deletion of TNS1 (TNS1f,f) and mice that express polymorphic TNS1 (TNS1W1197R). TNS1f,f mice will then be crossed with existing mice that express Cre- recombinase to allow for global or tissue restricted deletion of TNS1. The response of these mice to tissue injury will then be characterized. This data will be critical for understanding how TNS1 mediates cell-matrix interactions and modifies ECM formation. This work will set the stage for subsequent studies that will directly probe the role of polymorphic TNS1 in lung homeostasis.
Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disease characterized by unrelenting scarring and stiffening of the lungs, and few FDA approved treatments. This proposal aims to determine the role that TNS1 plays in the development of pulmonary fibrosis through the use of sophisticated transgenic animal models. Through these studies, new therapies may emerge in order to ameliorate the treatment of this deadly disorder.
| Bernau, Ksenija; Leet, Jonathan P; Esnault, Stephane et al. (2018) Eosinophil-degranulation products drive a proinflammatory fibroblast phenotype. J Allergy Clin Immunol 142:1360-1363.e3 |
| Bernau, Ksenija; Torr, Elizabeth E; Evans, Michael D et al. (2017) Tensin 1 Is Essential for Myofibroblast Differentiation and Extracellular Matrix Formation. Am J Respir Cell Mol Biol 56:465-476 |
| Esnault, Stephane; Bernau, Ksenija; Torr, Elizabeth E et al. (2017) RNA-sequencing analysis of lung primary fibroblast response to eosinophil-degranulation products predicts downstream effects on inflammation, tissue remodeling and lipid metabolism. Respir Res 18:188 |
