Inflammatory microenvironment and endothelial to mesenchymal transition (EndMT) are two key factors in the development of fibrosis. We had designed and synthesized a variety of structural modifications of rutaecarpine (RUT) and found a novel derivative of RUT, 10-Fluoro-2- methoxy-rutaecarpine (F-RUT), showing well anti-inflammation activity with very low cytotoxicity in endothelial cells. However, the pharmacological effect and molecular target of F-RUT in fibrosis are not known. In this proposal, we aim to validate the effects of F-RUT on inflammation and EndMT during the development of fibrosis in mice and understand its mechanisms in molecular levels. We will use KLF10-deficient mice, a lung fibrosis animal model with high inflammatory index, as an in vivo platform to evaluate the effect of F-RUT on inflammation. The secreted inflammatory cytokines will become invasive traits by inducing EndMT. Furthermore, the effects of F-RUT on the detail hallmarks and the phenotypic cell migration and invasion will be examined using a TGF-β-induced EndMT model system. We also found that the general small ubiquitin-like modifier-(SUMO)ylation status in cells was decreased upon F-RUT treatment. The role of F-RUT on sumoylated modulation for EndMT blockage will be further addressed. The targets of SUMO-modulation modulated by F-RUT treatment will be identified to establish the correlation of sumoylation and inflammatory EndMT. Appropriate inhibitors of the pathways will also be implemented to validate the role of F-RUT on SUMO-modulation. This results of this project will provide the molecular linkages of inflammation, EndMT and fibrosis. Furthermore, it will demonstrate novel mechanisms for the inhibitory effect of F-RUT on the inflammation and EndMT. This will also provide an updated strategy for fibrosis blockade.
|Effective start/end date||8/1/14 → 12/31/15|
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