Title: The role of Hedgehog signalling in potentiating Th2 immune pathology in asthma
Funder: Asthma UK

Abstract: In this study we will investigate a new approach for the treatment of asthma. This will involve laboratory-based research on the immune system and lungs in humans and mice. Why do we need to continue funding scientific research into asthma? Over five million people in the UK suffer from asthma, some of whom have chronic and disabling symptoms, despite the best treatments available today. Laboratory research into asthma aims to understand how healthy lungs function and what goes wrong when asthma develops. New information on how the lungs work will allow us to design and test ideas for new or improved asthma treatments. What happens to the lung during allergic asthma? Allergic asthma is a complex long-term disorder, where substances called allergens (such as animal fur/skin, pollen or house-dust mite droppings) irritate the airways, causing them to tighten and become inflamed. This leads to wheezing, coughing and mucus production, and sadly can sometimes provoke life-threatening asthma attacks. These symptoms are caused by the response of the body’s immune system to an allergen. The white blood cells of our immune system (immune cells) protect us from infection by reacting to harmful viruses and bacteria. However, immune cell reactions to allergens are inappropriate and unwanted because allergens should be harmless substances to us. It is not really understood why some people are particularly prone to making allergic-type immune responses. The study of the immune system in asthma and allergy is therefore important to understanding why these disorders occur. What is the aim of the proposed research idea? Our aim is to find a new way to interfere with allergic immune responses in asthmatic lungs, so that we can minimise them. We will test our idea that these unwanted responses can be controlled by altering the function of a particular set of genes. These genes make proteins called Hh proteins. We have already completed some experiments showing that Hh proteins are increased in the lungs of mice with the mouse version of asthma. We also found that Hh proteins cause allergic-type immune cells (present in the lung) to become more active. So, Hh proteins in the lungs of asthmatics may be making symptoms worse. Why is this an important new idea? If our ideas are correct, drugs could be used to interfere with the activity of Hh proteins in the lung of asthmatics, decreasing unwanted immune responses, and improving symptoms This is a new approach because no one has ever studied the action of Hh proteins on asthmatic immune responses. Many asthma sufferers rely on steroid drugs, which can have significant side-effects. We therefore urgently need new ways to target asthma symptoms Additionally, we have recently obtained a patent based on our initial experiments, showing that there is strength in our idea, making further investigation worthwhile. What are the objectives of the research? Firstly, we will study the effects of Hh proteins on allergic immune responses in the lungs of mice that have been given an asthma-like disease. During these experiments we can give the mice various treatments to decrease Hh proteins, and monitor their lungs over time. We will also use sophisticated genetically-modified (GM)-mice to test the effect of removing the genes that make Hh proteins, on the severity of disease. Secondly, to extend our mouse experiments, we will study whether Hh proteins are present in human lungs. We have established links with doctors at Papworth Hospital, who will give us lung samples from asthmatic and non-asthmatic patients attending their lung disease clinic. We will also analyse human lung samples obtained from a commercial cell-bank. Additionally, we will investigate the effect of Hh proteins on human immune cells by taking small blood samples from healthy people to perform experiments on in the laboratory. This part of the project can be done in our own institution, Great Ormon


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY