title: Design, Assessment, and in vivo Evaluation of a Computational Model Illustrating the Role of CAV1 in CD4(+) T-lymphocytes.
abstract: Caveolin-1 (CAV1) is a vital scaffold protein heterogeneously expressed in both healthy and malignant tissue. We focus on the role of CAV1 when overexpressed in T-cell leukemia. Previously, we have shown that CAV1 is involved in cell-to-cell communication, cellular proliferation, and immune synapse formation; however, the molecular mechanisms have not been elucidated. We hypothesize that the role of CAV1 in immune synapse formation contributes to immune regulation during leukemic progression, thereby warranting studies of the role of CAV1 in CD4(+) T-cells in relation to antigen-presenting cells. To address this need, we developed a computational model of a CD4(+) immune effector T-cell to mimic cellular dynamics and molecular signaling under healthy and immunocompromised conditions (i.e., leukemic conditions). Using the Cell Collective computational modeling software, the CD4(+) T-cell model was constructed and simulated under CAV1 (+/+), CAV1 (+/-), and CAV1 (-/-) conditions to produce a hypothetical immune response. This model allowed us to predict and examine the heterogeneous effects and mechanisms of CAV1 in silico. Experimental results indicate a signature of molecules involved in cellular proliferation, cell survival, and cytoskeletal rearrangement that were highly affected by CAV1 knock out. With this comprehensive model of a CD4(+) T-cell, we then validated in vivo protein expression levels. Based on this study, we modeled a CD4(+) T-cell, manipulated gene expression in immunocompromised versus competent settings, validated these manipulations in an in vivo murine model, and corroborated acute T-cell leukemia gene expression profiles in human beings. Moreover, we can model an immunocompetent versus an immunocompromised microenvironment to better understand how signaling is regulated in patients with leukemia.
authors.affiliation: Department of Biology, University of Nebraska at Omaha , Omaha, NE , USA.
authors.forename: Brittany D
authors.initials: BD
authors.lastname: Conroy
authors.affiliation: Department of Biology, University of Nebraska at Omaha , Omaha, NE , USA.
authors.forename: Tyler A
authors.initials: TA
authors.lastname: Herek
authors.affiliation: Department of Biology, University of Nebraska at Omaha , Omaha, NE , USA.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Shew
authors.affiliation: Department of Biology, University of Nebraska at Omaha , Omaha, NE , USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Latner
authors.affiliation: Department of Biology, University of Nebraska at Omaha , Omaha, NE , USA.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Larson
authors.affiliation: Department of Biology, University of Nebraska at Omaha , Omaha, NE , USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Allen
authors.affiliation: Department of Biology, University of Nebraska at Omaha , Omaha, NE , USA.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Davis
authors.affiliation: Department of Biochemistry, University of Nebraska at Lincoln , Lincoln, NE , USA.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Helikar
authors.affiliation: Department of Biology, University of Nebraska at Omaha , Omaha, NE , USA.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Cutucache
keywords: CD4+ T-lymphocyte; adult T-cell leukemia; caveolin-1; computational biology; immunosuppression; immunotherapy; logical models; the cell collective