Mathematical model of activation of transforming growth factor - β1 with application to liver fibrosis progression
Transforming growth factor-β1 (TGF-β1) plays important roles in diverse cellular programs and extracellular activation of TGF-β1 from its latent form is an important stage in its physiological regulation. Plasmin has long been accepted as an activator of TGF-β1, but experimental data using in vivo f...
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| Format: | Thesis |
| Language: | English |
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2014
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| Online Access: | http://hdl.handle.net/10356/60570 |
| _version_ | 1826116485796331520 |
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| author | Venkatraman, Lakshmi |
| author2 | Sourav Saha Bhowmick |
| author_facet | Sourav Saha Bhowmick Venkatraman, Lakshmi |
| author_sort | Venkatraman, Lakshmi |
| collection | NTU |
| description | Transforming growth factor-β1 (TGF-β1) plays important roles in diverse cellular programs and extracellular activation of TGF-β1 from its latent form is an important stage in its physiological regulation. Plasmin has long been accepted as an activator of TGF-β1, but experimental data using in vivo fibrosis models, indicates that plasmin can negatively regulate TGF-β1 levels. In an effort to understand the role of plasmin in TGF-β1 activation, we first built a computational model of plasmin activation by urokinase. Ordinary differential equations were constructed to model the conversion of precursor plasminogen into active plasmin. Computational simulations and bifurcation analysis predicted a bistable system which was tested using cell-free experiments with recombinant proteins. Our results indicated that ultrasensitive, bistable activation of urokinase-plasmin is possible in the presence of substrate competition. We next built a computational model including both plasmin activation and plasmin mediated TGF-β1 activation. We find in computational modeling that at a systems level, plasmin can cause a cooperative, switch-like decrease in TGF-β1 activation. Model predictions were tested using co-culture models of hepatocytes and hepatic stellate cells treated with plasminogen. Treated cells displayed decreased activation of TGF-β1 with sigmoidal dose-response and hysteresis. This decline was accompanied by degradation of thrombospondin-1, an important physiological activator of TGF-β1 that can be cleaved by plasmin. Antagonistic interplay between plasmin and thrombospondin-1 is an important feature of our model, and is confirmed by our experiments. These results suggest novel mechanisms and hidden pitfalls for addressing TGFβ-related diseases, and provide a new explanation for a puzzling behavior in fibrosis. |
| first_indexed | 2024-10-01T04:12:31Z |
| format | Thesis |
| id | ntu-10356/60570 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T04:12:31Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | ntu-10356/605702020-11-01T11:30:21Z Mathematical model of activation of transforming growth factor - β1 with application to liver fibrosis progression Venkatraman, Lakshmi Sourav Saha Bhowmick School of Computer Science and Engineering Singapore-MIT Alliance Programme DRNTU::Engineering::Computer science and engineering Transforming growth factor-β1 (TGF-β1) plays important roles in diverse cellular programs and extracellular activation of TGF-β1 from its latent form is an important stage in its physiological regulation. Plasmin has long been accepted as an activator of TGF-β1, but experimental data using in vivo fibrosis models, indicates that plasmin can negatively regulate TGF-β1 levels. In an effort to understand the role of plasmin in TGF-β1 activation, we first built a computational model of plasmin activation by urokinase. Ordinary differential equations were constructed to model the conversion of precursor plasminogen into active plasmin. Computational simulations and bifurcation analysis predicted a bistable system which was tested using cell-free experiments with recombinant proteins. Our results indicated that ultrasensitive, bistable activation of urokinase-plasmin is possible in the presence of substrate competition. We next built a computational model including both plasmin activation and plasmin mediated TGF-β1 activation. We find in computational modeling that at a systems level, plasmin can cause a cooperative, switch-like decrease in TGF-β1 activation. Model predictions were tested using co-culture models of hepatocytes and hepatic stellate cells treated with plasminogen. Treated cells displayed decreased activation of TGF-β1 with sigmoidal dose-response and hysteresis. This decline was accompanied by degradation of thrombospondin-1, an important physiological activator of TGF-β1 that can be cleaved by plasmin. Antagonistic interplay between plasmin and thrombospondin-1 is an important feature of our model, and is confirmed by our experiments. These results suggest novel mechanisms and hidden pitfalls for addressing TGFβ-related diseases, and provide a new explanation for a puzzling behavior in fibrosis. Doctor of Philosophy (SCE) 2014-05-28T07:34:37Z 2014-05-28T07:34:37Z 2011 2011 Thesis http://hdl.handle.net/10356/60570 en 181 p. application/pdf |
| spellingShingle | DRNTU::Engineering::Computer science and engineering Venkatraman, Lakshmi Mathematical model of activation of transforming growth factor - β1 with application to liver fibrosis progression |
| title | Mathematical model of activation of transforming growth factor - β1 with application to liver fibrosis progression |
| title_full | Mathematical model of activation of transforming growth factor - β1 with application to liver fibrosis progression |
| title_fullStr | Mathematical model of activation of transforming growth factor - β1 with application to liver fibrosis progression |
| title_full_unstemmed | Mathematical model of activation of transforming growth factor - β1 with application to liver fibrosis progression |
| title_short | Mathematical model of activation of transforming growth factor - β1 with application to liver fibrosis progression |
| title_sort | mathematical model of activation of transforming growth factor β1 with application to liver fibrosis progression |
| topic | DRNTU::Engineering::Computer science and engineering |
| url | http://hdl.handle.net/10356/60570 |
| work_keys_str_mv | AT venkatramanlakshmi mathematicalmodelofactivationoftransforminggrowthfactorb1withapplicationtoliverfibrosisprogression |