Defense Date

2025

Document Type

Thesis

Degree Name

Master of Science

Department

Biomedical Engineering

First Advisor

Christopher Lemmon

Second Advisor

Rebecca Heise

Third Advisor

Preetam Ghosh

Abstract

The induction of Epithelial Mesenchymal Transition (EMT) is initiated by a

number of protiens and growth factors, one of which is the profibrotic cytokine Trans-

forming Growth Factor β (TGF-β). Within the extracellular matrix (ECM), TGF-β

is found in a latent, inactive form bound to proteins such as fibronectin (FN). For

TGF-β to contribute to EMT induction, it has to be extracted from the latent com-

plexes into a soluble form. This soluble, activated TGF-β can then bind to receptors

on the cell membrane, which causes the transduction of signals that begin EMT. Re-

search has shown that the release of soluble TGF-β is mediated by integrins on the

cell membrane. The binding of the Latency Associated Peptide (LAP) and of soluble

FN to integrins αv and α5 respectively triggers the activation of motor and formin

proteins that contribute to the assembly of ECM and contract to release soluble, ac-

tive TGF-β from the latent complexes. While there is extensive research on the roles

of TGF-β and integrin signaling in inducing EMT, the synergistic effects of the two

remain unexplored. To investigate the combinatorial effects of the two, we developed

viiia deterministic model simulating the integrin-mediated unfolding of the complexes

that release active TGF-β that can then bind to receptors to induce EMT signaling

A deterministic model consisting of 13 ODEs was developed representing the

unfolding of latent TGF-β and the binding of fibronectin and the latent TGF-β com-

plexes with transmembrane integrins using the compiled results of numerous experi-

mental studies. A combination of rate law kinetics and the Hill activation equation

were used to develop the model, and rates were optimized using steady state values

derived experimentally or from assumptions based on knowledge of the behavior of

the variables. The model was validated by running simulations mimicking the treat-

ment of MCF10A human breast cells with soluble TGF-β and comparing the final

concentrations of the components of the system. Simulations of the inhibition of in-

tegrin activity were then run to use the model to predict the extent of influence of

integrin signaling in the progression of the system.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-9-2025

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