Final Report Summary - DYNASTIIC (Dynamic Signal Transduction in Individual Cells)
Regulation of proliferation and differentiation is a fundamental challenge for multicellular organisms. The decision between alternative cell fates is therefore tightly controlled by cellular signalling. During the past decades, the central components of the signalling machinery have been identified. The challenge we are facing now is to understand how signalling networks act dynamically in living cells and how they intersect with each other to control the physiological response of a cell. Since signalling networks contain complex, non-linear interactions that are difficult to understand intuitively, it is important to use an interdisciplinary approach, combining quantitative experiments and theoretical analysis. As cellular decisions often vary even in genetically identical cells depending on the initial conditions and the micro-environment, we have to measure signalling on the level of individual cells.
The aim of the present project is to investigate the dynamics of TGFbeta signalling, a pathway controlling proliferation and migration in epithelial cells. We generated a reporter system that allowed us to measure pathway activity in individual living cells with high temporal and spatial resolution. Using automated image analysis, analysis methods from speech recognition, statistical methods and information theory, we quantified the response of thousands of cells to varying concentrations of ligands and found that cells responded heterogeneously to a given input. These cell-specific responses were determined by the state of the cell, specifically by the concentration of signalling proteins. As a consequence, signalling dynamics could be decomposed into distinct classes representing responses of varying strength and duration, which determined the cellular outcome of the signal transmission process. We established a strategy for mathematical modelling that allowed us to quantitatively reproduce heterogeneous signalling in populations of single cells and to predict molecular mechanisms that determine decomposition of signalling responses. Using experimental approaches such as genomic engineering, we could validate these predictions and identify feedback by SMAD7 as an important regulator of cell-specific responses to TGFbeta.
After a postdoc at Harvard Medical School, the Marie Curie Career Integration Grant helped the fellow to establish his own independent research group in Europe and integrate into the European research community. During this report period, the fellow accepted a faculty position at a European university, leading to stable permanent position in research. In addition, the grant allowed the fellow to start several national and international collaborations, participate in international workshops and symposia and successfully apply for additional third-party grants. At the same time, knowledge was transferred back to Europe by training students through various means.
The aim of the present project is to investigate the dynamics of TGFbeta signalling, a pathway controlling proliferation and migration in epithelial cells. We generated a reporter system that allowed us to measure pathway activity in individual living cells with high temporal and spatial resolution. Using automated image analysis, analysis methods from speech recognition, statistical methods and information theory, we quantified the response of thousands of cells to varying concentrations of ligands and found that cells responded heterogeneously to a given input. These cell-specific responses were determined by the state of the cell, specifically by the concentration of signalling proteins. As a consequence, signalling dynamics could be decomposed into distinct classes representing responses of varying strength and duration, which determined the cellular outcome of the signal transmission process. We established a strategy for mathematical modelling that allowed us to quantitatively reproduce heterogeneous signalling in populations of single cells and to predict molecular mechanisms that determine decomposition of signalling responses. Using experimental approaches such as genomic engineering, we could validate these predictions and identify feedback by SMAD7 as an important regulator of cell-specific responses to TGFbeta.
After a postdoc at Harvard Medical School, the Marie Curie Career Integration Grant helped the fellow to establish his own independent research group in Europe and integrate into the European research community. During this report period, the fellow accepted a faculty position at a European university, leading to stable permanent position in research. In addition, the grant allowed the fellow to start several national and international collaborations, participate in international workshops and symposia and successfully apply for additional third-party grants. At the same time, knowledge was transferred back to Europe by training students through various means.