Abstract
BackgroundOne of the greatest challenges facing biomedical research is the integration and sharing of vast amounts of information, not only for individual researchers, but also for the community at large. Agent Based Modeling (ABM) can provide a means of addressing this challenge via a unifying translational architecture for dynamic knowledge representation. This paper presents a series of linked ABMs representing multiple levels of biological organization. They are intended to translate the knowledge derived from in vitro models of acute inflammation to clinically relevant phenomenon such as multiple organ failure.Results and DiscussionABM development followed a sequence starting with relatively direct translation from in-vitro derived rules into a cell-as-agent level ABM, leading on to concatenated ABMs into multi-tissue models, eventually resulting in topologically linked aggregate multi-tissue ABMs modeling organ-organ crosstalk. As an underlying design principle organs were considered to be functionally composed of an epithelial surface, which determined organ integrity, and an endothelial/blood interface, representing the reaction surface for the initiation and propagation of inflammation. The development of the epithelial ABM derived from an in-vitro model of gut epithelial permeability is described. Next, the epithelial ABM was concatenated with the endothelial/inflammatory cell ABM to produce an organ model of the gut. This model was validated against in-vivo models of the inflammatory response of the gut to ischemia. Finally, the gut ABM was linked to a similarly constructed pulmonary ABM to simulate the gut-pulmonary axis in the pathogenesis of multiple organ failure. The behavior of this model was validated against in-vivo and clinical observations on the cross-talk between these two organ systemsConclusionA series of ABMs are presented extending from the level of intracellular mechanism to clinically observed behavior in the intensive care setting. The ABMs all utilize cell-level agents that encapsulate specific mechanistic knowledge extracted from in vitro experiments. The execution of the ABMs results in a dynamic representation of the multi-scale conceptual models derived from those experiments. These models represent a qualitative means of integrating basic scientific information on acute inflammation in a multi-scale, modular architecture as a means of conceptual model verification that can potentially be used to concatenate, communicate and advance community-wide knowledge.
Highlights
One of the greatest challenges facing biomedical research is the integration and sharing of vast amounts of information, for individual researchers, and for the community at large
These models represent a qualitative means of integrating basic scientific information on acute inflammation in a multi-scale, modular architecture as a means of conceptual model verification that can potentially be used to concatenate, communicate and advance community-wide knowledge
Reference model for the epithelial barrier agent based model (EBABM) and validation experiments The reference model for the EBABM is a well-described human cultured enterocyte model (Caco-2) and its responses to inflammatory mediators including nitric oxide (NO) and a pro-inflammatory cytokine mix ("cytomix") that includes tumor necrosis factor (TNF), interleukin-1 (IL-1) and interferon-gamma (IFN-gamma) [24,25,26]. These papers suggest that enterocyte tight junction (TJ) proteins are involved in the integrity of gut epithelial barrier function, and that the production and localization of TJ proteins are impaired in a pro-inflammatory cytokine milieu
Summary
One of the greatest challenges facing biomedical research is the integration and sharing of vast amounts of information, for individual researchers, and for the community at large. The mirroring of these multiple levels in the organization of biomedical research has led to a disparate and compartmentalized community and resulting organization of data The consequences of this are seen primarily in attempts to develop effective therapies for diseases resulting from disorders of internal regulatory processes. There has been growing interest in the study of inflammation as a common underlying mechanism in disease processes ranging from sepsis to atherosclerosis (as noted by the recent addition of inflammation as an Emphasis Area to the NIH Roadmap for Medical Research) The investigation of such a ubiquitous process presents significant challenges in the integration and concatenation of research efforts in both the "vertical" and "horizontal" directions
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
