Biology subjects

Tserunyan, V.

Publications and source records attributed to Tserunyan, V..

4 recordsLinked to original sources

bioRxiv2023

Information-theoretic analysis of a model of CAR-4-1BB-mediated NFκB activation

Systems biology utilizes computational approaches to examine an array of biological processes, such as cell signaling, metabolomics and pharmacology. This includes mathematical modeling of CAR T cells, a modality of cancer therapy by which genetically engineered immune cells recognize and combat a cancerous target. While successful against hematologic malignancies, CAR T cells have shown limited success against other cancer types. Thus, more research is needed to understand their mechanisms of action and leverage their full potential. In our work, we set out to apply information theory on a mathematical model of cell signaling of CAR-mediated activation following antigen encounter. First, we estimated channel capacity for CAR-4-1BB-mediated NF{kappa}B signal transduction. Next, we evaluated the pathways ability to distinguish contrasting "low" and "high" antigen concentration levels, depending on the amount of intrinsic noise. Finally, we assessed the fidelity by which NF{kappa}B activation reflects the encountered antigen concentration, depending on the prevalence of antigen-positive targets in tumor population. We found that in most scenarios, fold change in the nuclear concentration of NF{kappa}B carries a higher channel capacity for the pathway than NF{kappa}Bs absolute response. Additionally, we found that most errors in transducing the antigen signal through the pathway skew towards underestimating the concentration of encountered antigen. Finally, we found that disabling IKK{beta} deactivation could increase signaling fidelity against targets with antigen-negative cells. Our information-theoretic analysis of signal transduction can provide novel perspectives on biological signaling, as well as enable a more informed path to cell engineering.

systems biology↗

bioRxiv2022

Computational analysis of 4-1BB-induced NF κB signaling suggests improvements to CAR cell design

BackgroundChimeric antigen receptor (CAR)-expressing cells are a powerful modality of adoptive cell therapy against cancer. The strength and dynamics of signaling events initiated upon antigen binding depend on the costimulatory domain within the structure of the CAR. One such costimulatory domain is 4-1BB, which affects cellular response via the NF{kappa}B pathway. However, the quantitative aspects of 4-1BB-induced NF{kappa}B signaling are not fully understood. MethodsWe developed an ordinary differential equation-based mathematical model representing canonical NF{kappa}B signaling activated by CAR-4-1BB. We first performed a global sensitivity analysis on our model to quantify the impact of kinetic parameters and initial protein concentrations. We ran Monte Carlo simulations of cell population-wide variability in NF{kappa}B signaling and used Kraskovs algorithm to quantify the mutual information between the extracellular signal and different levels of the NF{kappa}B signal transduction pathway. ResultsWe determined that in response to a wide range of antigen concentrations, the magnitude of the transient peak in the nuclear concentration of NF{kappa}B varies significantly, while the timing of this peak is relatively consistent. Our global sensitivity analysis showed that the model is robust to variations in parameter values, and thus, its quantitative predictions would remain applicable to a broad range of parameter values. Next, we found that overexpressing NEMO and disabling IKK{beta} deactivation are predicted to increase the mutual information between antigen levels and NF{kappa}B activation. ConclusionsOur modeling predictions provide actionable insights to guide CAR development. Particularly, we propose specific manipulations to the NF{kappa}B signal transduction pathway that can fine-tune the response of CAR-4-1BB cells to the antigen concentrations they are likely to encounter.

systems biology↗

bioRxiv2022

Modeling predicts differences in CAR T cell signaling due to bio-logical variability

In recent decades, chimeric antigen receptors (CARs) have been successfully used to generate engineered T cells capable of recognizing and eliminating cancer cells. The structure of CARs frequently includes costimulatory domains, which enhance the T cell response upon antigen encounter. However, it is not fully known how the CAR co-stimulatory domains influence T cell activation in the presence of biological variability. In this work, we used mathematical modeling to elucidate how the inclusion of one such co-stimulatory molecule, CD28, impacts the response of a population of engineered T cells under different sources of variability. Particularly, our simulations demonstrate that CD28-bearing CARs mediate a faster and more consistent population response under both target antigen variability and kinetic rate variability. We identify kinetic parameters that have the most impact on mediating cell activation. Finally, based on our findings, we propose that enhancing the catalytic activity of lymphocyte-specific protein tyrosine kinase (LCK) can result in drastically reduced and more consistent response times among heterogeneous CAR T cell populations.

systems biology↗

bioRxiv2019

Microtubules stabilize intercellular contractile force transmission during tissue folding

During development, forces transmitted between cells are critical for sculpting epithelial tissues. Actomyosin contractility in the middle of the cell apex (medioapical) can change cell shape (e.g., apical constriction), but can also result in force transmission between cells via attachments to adherens junctions. How actomyosin networks maintain attachments to adherens junctions under tension is poorly understood. Here, we discovered that microtubules stabilize actomyosin intercellular attachments in epithelia during Drosophila mesoderm invagination. First, we used live imaging to show a novel arrangement of the microtubule cytoskeleton during apical constriction: medioapical, non-centrosomal Patronin (CAMSAP) foci formed by actomyosin contraction organizes an apical microtubule network. Microtubules were required for mesoderm invagination but were not necessary for apical contractility or adherens junction assembly. Instead, microtubules promoted the stable connection between medioapical actomyosin and adherens junctions. These results define a role for coordination between actin and microtubule cytoskeletal systems in intercellular force transmission and tissue morphogenesis.

developmental biology↗