Characterizing the Programmatic Response to the Small Molecule Inhibitor, Halofuginol, in a TGFB-Induced Fibroblast
Powers, Kristen E.
MetadataShow full item record
CitationPowers, Kristen E. 2019. Characterizing the Programmatic Response to the Small Molecule Inhibitor, Halofuginol, in a TGFB-Induced Fibroblast. Master's thesis, Harvard Extension School.
AbstractThe use of small molecule tRNA-synthetase inhibitors has garnered attention for their ability to act as therapeutics for a variety of diseases. Halofuginone and its less toxic analog, Halofuginol, are tRNA-synthetase inhibitors that are currently being investigated by our lab for their ability to dampen cytokine-driven, pathogenic tissue remodeling programs in diverse tissues. While the molecular target of these molecules has been identified, the mechanism of action remains unclear. It is known that HF can activate the amino acid response (AAR) pathway while hindering cytokine-induced pathogenic tissue remodeling. Our group has found that HF can elicit its therapeutic action, including anti-inflammatory and anti-fibrotic effects, independent of the AAR sensor and effector, general control nonderepressible 2 (GCN2).
The work in this thesis characterized the role of HFol in the pulmonary lung fibroblastic cell line, LL29. In this work Halofuginol was shown to activate the canonical AAR in the pulmonary lung fibroblastic cell line, LL29, by inducing the phosphorylation of GCN2 and eIF2a. Specifically, this project used global transcriptomic and proteomic profiling to characterize the programmatic response to HFol in LL29 cells stimulated with the profibrotic cytokine, TGFB. We found that HFol can suppress many of the profibrotic transcriptional and translational effects in this system. We also found that in the LL29 cells HFol does not disrupt the TGFB-induced phosphorylation of Smad proteins. Additionally, we began to characterize the transcriptional effects of HFol that are independent of GCN2 kinase activity. Together, this thesis deepens our current understanding of how HFol functions to modulate the profibrotic program in a fibroblastic cell line.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42004211
- DCE Theses and Dissertations