Towards systems biology analysis of multi-scale inflammatory signalling

Since the discovery of the first vaccine by Edward Jenner over 200 years ago, a major challenge in immunology has been to understand how an organism can protect itself against infections caused by foreign microorganisms such as viruses or parasites. We know now that the first line of defence against such threats is served by an innate immune system, which fights against invaders. However, a prolonged immune response is not beneficial for the organism and often contributes to various chronic diseases such as rheumatoid arthritis or asthma. Therefore, understanding the balance between the ability of the immune system to rapidly detect and remove foreign threats and to efficiently stop immune signalling is a fundamental yet not fully understood aspect of immunology. Inflammatory processes have been studied for years at the organism level (for example periodic fevers during malarial infections). However, it is critical to appreciate that inflammation starts from single cells that make up tissues. A cell has a range of sensors and intracellular mechanisms, which may recognise signals and respond by activating protective programmes. These aim to defend the infected cell, but also to warn neighbouring cells about incoming threats and shielding whole tissues from damage. Communication between such individual cells is controlled by group of small protein molecules, called cytokines that are produced and released into the extracellular environment. My recent theoretical work has predicted that even small changes in the timing of single-cell cytokine production might substantially affect the tissue-level inflammatory signalling. This perhaps suggests a new and exciting way of treating inflammatory disease. However in order to achieve it, a better understanding of the connection between single-cell behaviour and apparent tissue level outcome (e.g., in the inflamed arthritic joint) is required. The main goal of this Fellowship programme is to develop novel theoretical and experimental approaches for the analysis of such multi-scale systems. These methods will build up an understanding of tissue-level behaviour by developing new computational models that will allow the generation of computer predictions. (These new approaches will be relevant to other biological systems.) In order to build a more complete picture of inflammation, I will incorporate various cell signalling pathways into these models. I will measure cytokine levels in order to characterise the most important factors during the inflammatory response. I will quantify and visualise inflammatory processes in living single cells under the microscope. These movies will be used to develop accurate and realistic single-cell and tissue-level mathematical models that will be analysed to understand the control of inflammatory signalling (e.g. by investigating how specific connections in the cytokine network contribute to the tissue-level response). As a result, potential targets can be identified and selected for experimental confirmation. The work in this project will contribute to the current understanding of the mechanisms that underlie the control of inflammatory signals. This will assist with the identification of more efficient treatments of inflammatory diseases.

I will develop an integrated systems biology programme aiming towards multi-scale analyses of complex biological systems. I previously applied mathematical modelling and live-cell imaging approaches to investigate the single-cell dynamics and function of the NF-kappaB system, a critical early mediator of inflammation. This work predicted that the tissue-level inflammatory signalling can be controlled through the subtle changes in single-cell dynamics through underlying genetic networks. Failure to resolve inflammation is often associated with diseases such as rheumatoid arthritis and asthma. Therefore, a key question is to quantitatively understand the control of inflammatory signalling in cells and tissues. In this Fellowship programme I will develop and apply a set of novel theoretical and experimental approaches based on my own experience, and the collaborators, expertise, and cutting-edge technologies available to me in Manchester. The theoretical work will develop: 1) Dynamical mathematical models of the cellular paracrine/autocrine network. 2) Assembly of single cell dynamical models describing interactions between key inflammatory transcription factors (such as STATs, IRFs and NF-kappaB) that can be used to interpret and direct experimental strategy, and provide experimentally-testable predictions. 3) State-of-the-art algorithms for stochastic spatial simulation and multi-scale models of inflammation. The experimental work will include quantitative cytokine profiling (for inference of paracrine/autocrine networks) and multi-parameter live-cell imaging (for visualisation of inflammatory interactions using custom-made microfluidic devices). Modelling and experimental approaches will be used iteratively to optimize experimental design. My goal is to understand this complex and non-linear system, in order to control inflammation and to treat inflammatory disease.

I am fully committed to increase the likelihood of potential impact of this Fellowship project. I have indentified the following areas of future impact: 1. Academics and Clinicians: This project is an interdisciplinary systems biology project that studies key regulatory steps associated with propagation and resolution of inflammation. By its very nature it is of interest to immunologists, biomedical scientists and clinicians who are working in the field of inflammatory diseases. Developed novel multi-scale models will allow work across scales from molecules, cells and tissue and investigate complex regulation of diverse biological systems. These approaches will improve currently available models due to increased depth of molecular description of single cell regulation. These approaches will be of interest to systems biologists and mathematicians. I will engage with academics through high impact publications, talks at major conferences and professional group website. Whenever possible models will be made widely available. 2. Engagement with identified beneficiaries: In this project I have several named key external and internal collaborators. The data and knowledge that we generate in this project will be made available to them to assist with further development of the current understanding of inflammatory processes. I also hope to be able to incorporate data available through these collaborations into models which will benefit all groups. 3. Instrumentation companies: My aspiration is to strongly engage with instrumentation companies in order to develop experimental platforms and processing algorithms for efficient visualisation of tissue-level dynamical processes. 4. Pharmaceutical industry: The project is important for understanding how drugs may better control the resolution of inflammatory signalling. I have had active contacts with J. Unitt from AstraZeneca who was a co-author on our recent Science paper. The development of modelling approaches that predict how new anti-inflammatory drugs may functionally change the dynamics and function of inflammatory responses is an important objective. 5. Public Understanding of Science and external public relations: The use of microscopy provides a visual platform for the development of public understanding of science (PUS) and systems biology approaches. I will engage with the University of Manchester Press Office to coordinate media publicity and will develop a personal professional website to publicize results to scientists and also to the general public. Within FLS in Manchester there is excellent support for PUS activities. 6. Training: I will contribute to increasing the depth of systems biology training. I was already involved in training a group of biologists in mathematical modelling in Liverpool and realize the need for interdisciplinary expertise in systems biology. I will closely work with the project's PDRA to transfer my expertise in interdisciplinary research and develop his career in systems biology. I also believe that I can make personal contributions to development of mammalian cell systems biology by driving strategic interdisciplinary initiatives, such as the 'Insults and Inflammation' initiative (led by W. Müller) that aims towards rational clinical intervention strategies to help treat inflammatory diseases. 7. Exploitation: I will continuously monitor for commercially exploitable information and knowledge. In this respect, University of Manchester has a defined procedure for assessment of opportunities. I was already approached by Dr. A. Carcon (Commercialisation Executive, Manchester's Intellectual Property Limited) and I'm now well aware of appropriate routes.