Understanding sepsis with human relevance: An integrative study using in vitro, in vivo and in silico models
Abstract
Exposure to weapons of mass destruction (WMD) that include chemical, biological and nuclear agents increase susceptibility to systemic infection (sepsis) from endogenous and exogenous organisms. Almost all drugs recently developed in animal models to treat sepsis have failed in clinical trials. Thus, there is a significant need for a rapid prescreening tools to determine if the response of therapeutics in animals is predictive of their response in humans. Recently, we developed and validated a novel biomimetic microfluidic assay (bMFA) that reproduces the white blood cell-endothelial cell interaction cascade in a single physiologically relevant three dimensional system, mimicking inflammatory response in vivo. The bMFA can serve as platform to identify cellular and functional species differences in drug responses between mice and humans and may provide important insight into the failure of compounds tested in mice to translate into viable therapeutics in humans. We will use our established animal model of sepsis along with the bMFA in vitro model to test the hypothesis that in sepsis, phenotypic differences impact leukocyte-endothelial interactions similarly in vivo and in vitro. We will also determine if the response of mouse cells to two candidate drugs in vitro is predictive of the response of an animal model of sepsis to these drugs. We will finally determine if in vitro mouse white blood cell-endothelial cell responses to drugs is predictive of the response of human cells to these drugs. We will analyze changes in protein expression (proteomic analysis) to develop a computer model of the inflammatory response to determine which components of the inflammatory signaling in mouse cells is preserved in human cells to guide the further optimization of bMFA and development of therapeutics for treatment of sepsis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 01, 2019
- Source ID
- HDTRA11910012
Entities
People
- Mohammad Kiani
Organizations
- Defense Threat Reduction Agency
- Temple University