Investigation of REVERBalpha as a therapeutic target in pulmonary fibrosis

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Idiopathic pulmonary fibrosis (IPF) is a lung disease that kills 5000 people a year in the UK with few effective treatments. Myofibroblasts are a key cell type in IPF, and I have discovered a new way to regulate them. Myofibroblasts are not normally found in healthy tissue but occur in response to injury. This development/ differentiation is partly under the control of key messengers secreted by epithelial cells or macrophages. The importance of myofibroblasts in IPF is shown by the pathological accumulation of these cells observed in biopsies from patients. Therefore an attractive treatment approach would be to inhibit the development of myofibroblasts, and their function potentially stopping disease progression and permit healing. I have discovered that an important cell regulator protein, REVERBalpha, can prevent the formation of myofibroblasts from normal, healthy lung cells. I now want to take this exciting development forward, to determine if targeting REVERBalpha is a viable treatment option for patients, potentially providing a life saving treatment. REVERBalpha belongs to a family of proteins called nuclear hormone receptors. REVERBalpha is a master regulator of the body's capacity to handle fats from the diet, targeting them for storage, or utilisation. In my previous MRC sponsored research I developed novel compounds that alter the function of REVERBalpha. I showed that these compounds can regulate the function of inflammatory cells from the human lung. I have now extended these findings and shown that these compounds stop the development of myofibroblasts in the lab. My proposed research will investigate the function of REVERBalpha in lung fibrosis. Initially I will examine how loss of REVERBalpha affects development of lung fibrosis in models of human fibrotic lung disease. I will then test how my novel "drug-like" small molecules can prevent fibrosis development. I have developed new resources to permit rapid progress in this area, including a new antibody which permits precise measurement of REVERBalpha protein levels in patients with lung fibrosis, comparing against normal, healthy lung tissue.I have also discovered that REVERBalpha can alter how cells manage their energy requirements, leading to distinct changes in a number of small molecules, including some types of fat, together termed metabolites. This is very relevant for IPF as I have also shown that some of these pulmonary metabolites can alter the differentiation of myofibroblasts. I therefore plan to sample metabolites in both healthy and diseased lungs in the same patient; this will allow me to identify metabolic changes caused by IPF. I then have the option of investigating candidate metabolites with the aim of discovering which are regulated by REVERBalpha and play a causative role in disease progression. Finally, I will apply new technology to investigate which genes in the lung cells are targets for REVERBalpha including how the regulation is managed and what the consequences are for the cell. This will identify new pathways and additional drug targets for further studies beyond the current fellowship. I have brought together an international collaboration of researchers to address this novel hypothesis, which provides added benefit by offering me a superb research training experience. Though the research will be mainly conducted in Manchester, researchers, both basic scientists and clinical investigators, from other parts of the U.K. as well as Toronto will also be involved. In summary, I will be exploring a potential treatment option for an increasingly common and fatal lung disease for which no effective treatments currently exist.