SP 1

Integrative Genetic Analysis and Biomathematical Modelling of Systemic Inflammation

Aim of this CAPSyS subproject is to develop a dynamical biomathematical model of systemic inflammation and extra-pulmonal organ deterioration in pneumonia. We first improve functional understanding of molecular-genetic modifiers of disease progression by biostatistical analysis of genetic, gene expression, and other molecular data in combination with clinical data and intermediate phenotypes available from PROGRESS and other patient cohorts. This analysis results in the identification of causal relationships. A mechanistic model of systemic disease dynamics and corresponding influence of genetic effects will be constructed by differential equation based modelling of cytokine and cell response of systemic inflammation in patients. Important information such as the early phase of infection are not available for patients – corresponding modelling will focus on the murine system. Appropriate experiments are performed in subproject 4. Results from murine modeling and data from the deep phenotyping cohort in subproject 2 will allow to refine the human model with the aim to incorporate the breakdown of barrier function in the lung during disease progression. The long-term goal is to develop mathematical models which allow to evaluate effects of molecular disease modifiers, different aspects of patient heterogeneity, and new therapeutic targets and strategies. Thus, we hope to contrubute to improvements in clinical research and in patient outcome.

Keywords: Biostatistic analysis, modeling, systemic inflammation,organ failure, intermediate phenotype,pneumonia