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http://hdl.handle.net/11375/24749
Title: | Investigating the Extracellular Matrix in Pulmonary Fibrosis |
Other Titles: | INVESTIGATING THE EXTRACELLULAR MATRIX’S ROLE IN PULMONARY FIBROSIS TO APPROPRIATELY MODEL DISEASE AND TEST ANTIFIBROTIC THERAPIES |
Authors: | Upagupta, Chandak |
Advisor: | Kolb, Martin |
Department: | Medical Sciences |
Keywords: | Extracellular Matrix;Idiopathic pulmonary fibrosis |
Publication Date: | 2019 |
Abstract: | IPF is a progressive disease, characterized by dysregulated fibrosis of the extracellular matrix (ECM). The pathobiology of the disease is still unknown, and the median survival post-diagnosis is about 3-5 years. The two current US FDA approved drugs for IPF (nintedanib and pirfenidone) slow, but fail to reverse, disease progression. There is cumulating research that suggests the ECM is an active player in fibrosis. In this thesis, we summarized the current knowledge of ECM-cell interactions in the context of pulmonary fibrosis. To gain more mechanistic insight into the ECM characteristics that dictate cell behavior, we established a 3D ECM ex vivo system to assess the nonfibrotic and fibrotic ECM’s effect on fibroblasts. The ECM appears to promote both pathological and physiological cellular changes, depending on its structural and compositional properties. We also used this 3D ex vivo system as a preclinical tool to test the effect of directly inhibiting mechanotransduction in the fibrotic ECM – fibroblast profibrotic relationship. Lastly, since the fibrotic ECM seems to play a key role in progressive fibrosis, we evaluate if researchers are appropriately using the bleomycin model by starting interventions after ECM fibrosis is established. Over the past decade in the field, there has been an overall improvement in the appropriate therapeutic timing. In the preventative studies, however, there is still an inadequate characterization of inflammation. There is also poor transparency of preclinical-bleomycin data for clinically tested interventions for IPF. Addressing these shortcomings may improve the utility of the model at predicting an intervention’s success in clinical trials. These findings illustrate the ECM’s role in driving pulmonary fibrosis. Therefore, the ECM should be further investigated to understand disease progression, and reproduced in preclinical models to test interventions. This will improve the transition of pathobiological findings into efficient drug development for this devastating disease. |
URI: | http://hdl.handle.net/11375/24749 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Upagupta_Chandak_B_2019Aug_PhD.pdf | 1.75 MB | Adobe PDF | View/Open |
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