Control of macrophage multinucleation in health and disease

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The proposed project specifically addresses the MRC Strategic Plan in the areas of "tissue disease and degeneration" and "molecular datasets and disease". Macrophages are cells of the immune system that can fuse to form giant cells with multiple nuclei in peripheral tissues and specialist bone-resorbing osteoclasts in the skeleton. The fundamental physiological process of multinucleation is poorly understood, but is essential for the normal immune response and regulation of bone mass. Granulomas containing multinucleated giant cells are classically seen in chronic inflammatory disorders and infectious diseases including Crohn's disease, sarcoidosis and tuberculosis, whilst increased osteoclastic bone resorption causes osteoporosis and underlies cancer-induced bone loss. We propose that genes driving macrophage multinucleation also control signalling pathways that are essential for normal bone turnover and the inflammatory response, but which are dysregulated in osteoporosis and chronic granulomatous disease. In this project we will investigate the molecular mechanisms controlling macrophage multinucleation in health and disease. We have previously described a network of 134 genes involved in macrophage multinucleation (MMnet), and will now identify the ten genes with the largest effect on macrophage multinucleation using a cell culture-based screening approach. We will next establish their physiological importance to bone and the immune system by analysing the effects of universal gene deletion. Two genes will be selected on the basis of their novelty, effect size, function, experimental tractability and relevance to human disease for detailed studies in which the genes will be deleted specifically in macrophages. Studies using established disease provocation models will then determine whether deletion of the two genes in macrophages protects against development of osteoporosis and chronic inflammatory disease. These studies will identify signalling pathways that play a fundamental role in the development and progression of granulomatous disease and provide a new understanding of macrophage biology in health and disease.