Systems level investigation of cell-to-cell communication and cellular heterogeneity in neutrophil apoptosis

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Detailed knowledge about molecules and pathways in immune biology has brought about targeted therapies. A prominent example are TNF-alpha blockers in treatment of rheumatoid arthritis. However, such new therapies have serious adverse effects and often evoke unexpected and undesired outcomes. One likely reason is that properties emerging from cellular heterogeneity and complex, stochastic cell communication networks confound efforts to develop effective therapies. An important objective of the proposed study is to explore a new strategy for investigating and rationalizing the design of cell communication networks at single-cell resolution. The new strategy combines hierarchic stochastic mathematical models with live-cell imaging. In that approach, time dependent distributions measured in vivo are directly used for modeling, e.g. the distribution of the time to apoptosis is used instead of considering the molecular steps of the apoptosis pathway in detail. Therefore, there is no need for determination of a large set of parameters, which is a bottleneck in many conventional modeling techniques. The long-ranging experience with combined experimental and computational biology of the hosting scientist (Prof. Altschuler, UTSW Dallas, USA), and the high-throughput imaging and image analysis pipeline at the host institute will be most valuable for a successful implementation of the new strategy. We will use data based hierarchic stochastic modeling for investigation of a network of immune cell communication with high relevance to medical applications: TNF-alpha mediated activation and apoptosis of mouse neutrophils. While timely arrival and activation of neutrophils is critical to effectively fight pathogens, delayed apoptosis of neutrophils is a primary cause of autoimmune diseases like chronic inflammation. The complex, stochastic regulation by TNF-alpha of this process is elusive and will be investigated in the proposed project. The new approach will permit to consider cellular heterogeneity in a data-based mathematical description of the neutrophil communication network. It will thus provide a sound basis for investigation of cell-to-cell communication in inflamed tissue. A long-term goal is optimization of targeted therapies, in particular of dosage, timing and adjunctive therapies for TNF-alpha inhibitors. Moreover, the project will reveal both specific and general properties of cell communication networks, and will explore methods that can be used to study other cellular interaction networks in future research.