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Defining TILRR regulation of distinct IL-1RI responses using systems biology

Reference	BB/J009687/1
Principal Investigator / Supervisor	Professor Eva Qwarnstrom
Co-Investigators / Co-Supervisors	Professor William Holcombe, Professor Endre Kiss-Toth
Institution	University of Sheffield
Department	Infection Immunity & Cardiovasc Disease
Funding type	Research
Value (£)	553,186
Status	Completed
Type	Research Grant
Start date	03/09/2012
End date	02/09/2015
Duration	36 months

Abstract

Host defence responses are induced through the Toll-like and IL-1 receptors and activated by ligand binding and system-specific co-receptors. This project uses systems biology to analyse the function of the IL-1 receptor type I (IL-1RI), and its control by its co-receptor TILRR. TILRR is a ubiquitously expressed spliced variant of FREM1, of the FRAS1 family, which is independently transcribed and translated. We have demonstrated that TILRR controls IL-1RI function and activation of NF-kB, and regulates inflammatory and anti-apoptotic responses by IL-1. Alanine-scanning mutagenesis identified mutants, which selectively control inflammation and survival signals through IL-1RI. Here we will use these mutants to identify events at the level of the receptor complex, which selectively direct downstream activities. The data will be included in a computational model of receptor function, and predictions from this will inform design of experiments on signal transduction and gene regulation. We will use robotic screening to identify key intermediates involved, and characterise a subset of these in functional assays. The data will be incorporated in our NF-kB model, which we have demonstrated faithfully represents the biological system. Key regulators, predicted by the model, will be included in microarray experiments to identify relevant changes in gene activation profiles, and data analyzed using work-flow and included in the model. We will use FLAME, use super computers, to make possible expansion of the model to a level where we can link receptor function with signal transduction and gene activity. Predictions will be tested in relevant wet experiments and results will inform the model, in multiple iterations, to yield a comprehensive in silico representation of the biological system. The results will provide a platform for future comprehensive investigations of cellular response and expand the use of agent based modelling and the FLAME framework.

Summary

The immune system is our defence against microorganisms such as bacteria. The immune/inflammatory system also controls repair, whether activated after microorganisms have been killing our cells, or induced because of physical damage such as cuts and wounds even if not accompanied by infection. The immune/inflammatory system is organised for defence, white cells circulate in your blood "on patrol" constantly on alert for invaders with base depots called lymph nodes, where they can be marshalled in large numbers and sent out for attack. Some white cells produce antibodies and some produce substances that kill microorganisms directly. The immune/inflammatory system is divided into 2 parts, innate and adaptive. The adaptive part learns to recognise the invading microorganisms, and makes special antibodies tailored to each disease-producing microorganism. For a more rapid response a front line defence is needed. This is the innate immune/inflammatory system. In so called inflammatory diseases, activators of these systems get produced without injury and infection and white cells are called into healthy tissue, and damage it. This occurs for example in heart disease and is the underlying mechanism inducing damage to joints in the disease called arthritis. To treat these diseases we need to find ways of shutting off the message to the activated cells. This project is the continuation of work we have been doing for many years on an inflammatory inducer called interleukin-1, which is particularly potent, and is known to contribute significantly to tissue damage. In our earlier studies we have identified a novel regulator of the defence system, which significantly enhances activities induced by interleukin-1. We have demonstrated that this regulator is present in various types of inflammatory cells including those that can potentially damage healthy tissue. In addition, we have shown that in order to increase interleukin-1 activities the novel regulator binds to a so called "signalling receptor", which is located on the surface of the cell, and controls inflammatory activities through the cell. In this project we are investigating how this new regulator interacts with the signalling receptor and how it changes its function. We are going to use this information to identify the events it triggers inside the cell, and which lead to changes in cell behaviour. This will improve our understanding of how signals by cytokines such as interleukin-1 are regulated, and how they increase activity in inflammatory cells. Such information will contribute to our knowledge of how these activities are controlled, how to moderate their effects, and ultimately how to develop specific treatments for inflammatory disease. Specific intervention is very important in controlling these events, as we need to have a certain level of functioning inflammatory responses in case of bacterial infection and/or we are in need of tissue repair. By moderating the novel regulator, we have the possibility of leaving the main system intact and functioning normally. We have recently obtained detailed information about which parts of the regulator are particularly potent. In this project we will use this information to investigate the consequences of activating and blocking this regulator and determine what cellular functions will be disturbed through the different parts of the protein. This will make it possible to ultimately design specific treatments for diseases characterised by abnormalities in these functions. State-of-the-art computational modelling will provide much clearer insights into the many processes involved in this very complex system, and predictions from the models will give us information, which we will use in future experimentation and drug development.

Impact Summary

Medicine and Biology Background We are investigating mechanisms driving cellular responses in the healthy organism. However, identification of events, which selectively perturb aspects of receptor function and response control, will improve our understanding of inflammatory dys-regulation, characterising disease as well as basic biological evens. This field of work is fundamental to multi-factorial inflammatory conditions, widespread heath problems in the aging population of the developed world. Dys-regulation of inflammatory responses is a determining factor in prevalent and costly diseases including atherosclerosis, which costs the UK government £30.6 billion/year (NHS publication care quality commission, Sept 2009) and arthritis and related diseases which cost nearly £6 billion /year (Arthritis care sheet, 2007). It is also a major factor in organ failures and a highly significant parameter in the prognosis of cancer. Host defence mechanisms are tightly controlled systems, activated through Toll-like and IL-1 receptors. Ligand binding and co-receptor recruitment determine the appropriate signal amplification and activation of downstream events. The potential for therapeutic targeting at the level of the receptor has been demonstrated by the major advances resulting from development of the anti-TNFs. Diseases such as arthritis and atherosclerosis contribute significantly to degradation of quality of life in the older population. The population as a whole and organisations such as the NHS will continue to benefit from advances in this area. Benefits 1. Expanding the range of treatments for inflammatory diseases offers significant promise in reducing the period of morbidity in the last years of life. Greater specificity as is expected to result from targeting the functional sites in TILRR, will bring a number of benefits, such as potentially reducing side effects etc. In addition, selective blocking of anti-apoptotic responses is expected to increase the efficacy of chemotherapy while maintaining normal defence mechanisms against infection. 2. The innate immune defence is also critical to pathogen resistance in plants and animals, therefore, results from these studies may also have the potential to contribute to agricultural biotech - for example by GM strategies that derive disease resistant crops, without the need for agents, potentially hazardous to the environment. An example might be flax or rape engineered to express elevated levels of the TIR family Rust Resistance Protein. Computer Science Background Successful detailed models of this system will be of great interest to researchers in systems biology because they will demonstrate the power of this approach, which can be used in any other types of system. The FLAME framework ensures that the model can be integrated with other related systems and is being used in labs worldwide. Benefits The models will be made public so that others can adapt and integrate them with their own systems. Companies such as Genesys, and epiGenesys, started by M. Holcombe, and others which develop software for a wide range applications, will benefit from expansion of the systems. Biotechnology and systems biology, as applied to human health and innovation have been identified by the DTI as a growth R&D area in the UK because of the potential market for treatments. Given the stated aim of both the EU and organisations such as Yorkshire Forward to develop a Biotechnology Cluster in South Yorkshire, and the aims of the Treasury to foster Bioscience R&D in the UK as a whole, the potential commercial use for our work fits well strategically.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	Immunology, Systems Biology
Research Priority	Systems Approach to Biological research
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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