title: Formal modeling and analysis of the MAL-associated biological regulatory network: insight into cerebral malaria.
abstract: The discrete modeling formalism of René Thomas is a well known approach for the modeling and analysis of Biological Regulatory Networks (BRNs). This formalism uses a set of parameters which reflect the dynamics of the BRN under study. These parameters are initially unknown but may be deduced from the appropriately chosen observed dynamics of a BRN. The discrete model can be further enriched by using the model checking tool HyTech along with delay parameters. This paves the way to accurately analyse a BRN and to make predictions about critical trajectories which lead to a normal or diseased response. In this paper, we apply the formal discrete and hybrid (discrete and continuous) modeling approaches to characterize behavior of the BRN associated with MyD88-adapter-like (MAL)--a key protein involved with innate immune response to infections. In order to demonstrate the practical effectiveness of our current work, different trajectories and corresponding conditions that may lead to the development of cerebral malaria (CM) are identified. Our results suggest that the system converges towards hyperinflammation if Bruton's tyrosine kinase (BTK) remains constitutively active along with pre-existing high cytokine levels which may play an important role in CM pathogenesis.
authors.affiliation: Research Centre for Modeling and Simulation, National University of Sciences and Technology, Islamabad, Pakistan. dr.ahmad.jamil@gmail.com
authors.forename: Jamil
authors.initials: J
authors.lastname: Ahmad
authors.forename: Umar
authors.initials: U
authors.lastname: Niazi
authors.forename: Sajid
authors.initials: S
authors.lastname: Mansoor
authors.forename: Umair
authors.initials: U
authors.lastname: Siddique
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Bibby
mesh_terms: D019295:Computational Biology / Q000379:methods*; D006801:Humans; D016779:Malaria, Cerebral / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008954:Models, Biological; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4