“Dysregulation of inflammatory pathways is strongly implicated in cancers and autoimmune diseases. The most consequential of these pathways involves the nuclear translocation of NF-kB, a transcription factor that induces the transcription of multiple proteins associated with cell survival, inflammation, proliferation and death. It is activated when the fibroblast growth factor-inducible 14 kDa protein (Fn14), a trimeric receptor recruits its ligand, TWEAK. Studies have shown that Fn14 is over-expressed in many tumors, the aggressiveness of which is often correlated with the degree of upregulation. Furthermore, TWEAK-Fn14 activation has been shown to result in persistent NF-kB activation. Using a mechanistic model of the signaling system, two specific features of the Fn14 pathway, (a) the ability of Fn14 constitutive signaling and (b) NF-kB induced de novo Fn14 expression were identified that give rise to positive feedback regulation and differentiate it from TNF-a receptor signaling. Further analysis revealed that stimulation of Fn14 by TWEAK may generate highly non-linear dynamics, including stable limit cycles and bistable responses. Another critical contributor to the Fn14 signaling dynamics was found to be TWEAK- dependent Fn14 trafficking dynamics. Rapid internalization allowed cells to show only transient NFkB activity while lack of internalization was a significant factor in maintaining the cell in a constitutively active state. Detailed study of Fn14 internalization, recycling and degradation allowed the creation of a more comprehensive signaling model which is capable of accounting for a wide range of Fn14 signaling behaviors observed in pathological tissues. The model was further used as a platform for in silico studies of the effects of potential targeted therapies on constitutively active cells such as those found in aggressive tumors. The model predicts that two conventional therapeutic approaches - Fn14 antagonists and anti-Fn14 siRNA - would provide unsatisfactory benefits while a novel approach involving targeted degradation of the receptor could be promising avenue for developing anti-Fn14 therapeutics”--Abstract, page iv.
Samaranayake, V. A.
Chemical and Biochemical Engineering
Ph. D. in Chemical Engineering
Missouri University of Science and Technology
Journal article titles appearing in thesis/dissertation
- Analysis of FN14-NF-kB Signaling Response Dynamics using a Mechanistic Model
- Development of a Comprehensive Tweak-FN14-NF-kB Signaling Model
x, 95 pages
© 2021 Jawahar Khetan, All rights reserved.
Dissertation - Open Access
Khetan, Jawahar, "An investigation on the regulation of the tweak–Fn14–NF-kB pathway" (2021). Doctoral Dissertations. 3007.