NONLIN-KB

"""Role of Nonlinear Dynamics of NF-kB in Inflammation"""

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 Obiettivo del progetto (Objective)

'NF-kB is a family of transcription factors that coordinately control hundreds of genes involved in many steps of inflammatory processes, from microbial killing to cancer. When inflammatory stimuli hit the cell surface, NF-kB undergoes several cycles of nucleus-to-cytoplasm translocations, resulting in oscillations of nuclear NF-kB concentrations and activity. At single cell level, live imaging and mathematical modeling suggest that NF-kB oscillations are selected over other non-oscillatory dynamics. At population level there is significant heterogeneity, mainly due to cell asynchrony. Mathematical models reproducing population heterogeneity indicate absence of coupling between dynamics of individual cells. This behaviour is thought to be adaptive by enabling a wider multiplicity of responses, but this has not been tested. Moreover, due to collective heterogeneity, the link of NF-kB dynamics to gene expression in a tissue as a whole is far from being clear. Analyses of mathematical models of the NF-kB system using my expertise on Nonlinear Dynamics and Chaos Theory showed that complex oscillatory population dynamics are possible. Furthermore, regimes for coherent collective behaviours (synchrony) can be found. These regimes entail the use of periodic stimulations with different intensities and/or periods, suggestive of acute and chronic inflammatory conditions. My project proposes to mathematically explore and experimentally validate complex population dynamics. In vivo quantitative imaging of NF-kB dynamics in GFP-p65 knock-in cells upon repetitive stimulations will provide data to build models on NF-kB collective behaviours. Transcription profiles of synchronized cells will be incorporated into the model. By increasing our understanding on NF-kB collective dynamics, we expect to contribute to strategies for the control of diseases with a huge social impact, like septic shock, autoimmune diseases and cancer, in which the deregulation of NF-kB plays a pivotal role'

Introduzione (Teaser)

The body is a highly non-linear system of systems, and the application of mathematical models can help to better understand certain behaviours. Non-linear dynamics has provided the basis of models of cellular inflammatory processes and insight into mechanisms.

Descrizione progetto (Article)

Inflammation is the external manifestation of the body's protective response to tissue damage or injury. Substances migrate to the site of damage to repair the surrounding tissue. On the flip side, chronic inflammation actually causes damage to tissues. It plays a role in a plethora of common diseases ranging from asthma to osteoarthritis.

Transcription factors that control gene expression play a role in the inflammatory response. Some members of the nuclear factor-kappaB (NF-kB) family regulate multiple steps. EU support of the project 'Role of nonlinear dynamics of NF-kB in inflammation' (NONLIN-KB) gave scientists the opportunity to study oscillations of NF-kB between the cytoplasm and the nucleus and to analyse them mathematically.

Experimentally, inducing and observing the oscillations required construction of a special setup for imaging of cells with fluorescently tagged NF-kB. The setup enables microfluidic perfusion of the cells with various biochemical factors and simultaneous imaging.

Quantifying the responses of hundreds of cells necessitated development of specialised software. The algorithms use quantifiers from non-linear dynamics theory to describe observed dynamics through a time-series analysis. The team faithfully reproduced experimental observations with a simplified model exploiting only three layers of regulation. It should be an important tool for predicting possible mechanisms of NF-kB regulation of transcription.

With these powerful tools in their hands, researchers discovered that the oscillations are much more complicated than previously thought. They can be periodic or not, and can also begin spontaneously in the absence of stimuli. Under many conditions, the cells can exhibit coordinated dynamics or synchronous NF-kB oscillations. However, in the presence of periodic stimuli, the coordinated behaviour can be quite heterogeneous across cells.

The drug dexamethasone commonly used to treat inflammatory diseases was observed for its effect on stimulation-induced oscillations. It not only modified the dynamics of oscillations but also the transcription profile, providing a potential switch to control inflammatory responses.

The multidisciplinary NONLIN-KB project applied non-linear dynamics to the study of intracellular fluctuations in space and time of a transcription factor controlling the inflammatory response. The models have provided insight into stimulus-induced changes and point to potential targets for therapy.