Scholarly Works, Chemical Engineering

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https://hdl.handle.net/10919/24288
Research articles, presentations, and other scholarship

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Browsing Scholarly Works, Chemical Engineering by Department "Biomedical Engineering and Sciences"

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    Effects of receptor clustering on ligand dissociation kinetics: Theory and simulations
    Gopalakrishnan, Mahima; Forsten-Williams, Kimberly; Nugent, Matthew A.; Täuber, Uwe C. (Cell Press, 2005-12-01)
    Receptor-ligand binding is a critical first step in signal transduction and the duration of the interaction can impact signal generation. In mammalian cells, clustering of receptors may be facilitated by heterogeneous zones of lipids, known as lipid rafts. In vitro experiments show that disruption of rafts significantly alters the dissociation of fibrbroblast growth factor-2 (FGF2) from heparan sulfate proteoglycans (HSPGs), co-receptors for FGF-2. In this article, we develop a continuum stochastic formalism to address how receptor clustering might influence ligand rebinding. We find that clusters reduce the effective dissociation rate dramatically when the clusters are dense and the overall surface density of receptors is low. The effect is much less pronounced in the case of high receptor density and shows nonmonotonic behavior with time. These predictions are verified via lattice Monte Carlo simulations. Comparison with FGF-2-HSPG experimental results is made and suggests that the theory could be used to analyze similar biological systems. We further present an analysis of an additional cooperative internal-diffusion model that might be used by other systems to increase ligand retention when simple rebinding is insufficient.
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    Transcriptomic Analysis of Hepatic Cells in Multicellular Organotypic Liver Models
    Tegge, Allison N.; Rodrigues, Richard R.; Larkin, Adam L.; Vu, Lucas T.; Murali, T. M.; Rajagopalan, Padmavathy (Springer Nature, 2018-07-27)
    Liver homeostasis requires the presence of both parenchymal and non-parenchymal cells (NPCs). However, systems biology studies of the liver have primarily focused on hepatocytes. Using an organotypic three-dimensional (3D) hepatic culture, we report the first transcriptomic study of liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs) cultured with hepatocytes. Through computational pathway and interaction network analyses, we demonstrate that hepatocytes, LSECs and KCs have distinct expression profiles and functional characteristics. Our results show that LSECs in the presence of KCs exhibit decreased expression of focal adhesion kinase (FAK) signaling, a pathway linked to LSEC dedifferentiation. We report the novel result that peroxisome proliferator-activated receptor alpha (PPAR alpha) is transcribed in LSECs. The expression of downstream processes corroborates active PPAR alpha signaling in LSECs. We uncover transcriptional evidence in LSECs for a feedback mechanism between PPAR alpha and farnesoid X-activated receptor (FXR) that maintains bile acid homeostasis; previously, this feedback was known occur only in HepG2 cells. We demonstrate that KCs in 3D liver models display expression patterns consistent with an anti-inflammatory phenotype when compared to monocultures. These results highlight the distinct roles of LSECs and KCs in maintaining liver function and emphasize the need for additional mechanistic studies of NPCs in addition to hepatocytes in liver-mimetic microenvironments.