Control of macrophage multinucleation in health and disease

拟议的项目具体涉及MRC战略计划中的"组织疾病和变性"和"分子数据集和疾病"领域。巨噬细胞是免疫系统的细胞，可以融合形成外周组织中具有多个核的巨细胞和骨骼中专门的骨吸收破骨细胞。多核化的基本生理过程知之甚少，但对正常免疫反应和骨量调节至关重要。含有多核巨细胞的肉芽肿通常见于慢性炎症性疾病和感染性疾病，包括克罗恩病、结节病和结核病，而骨细胞骨吸收增加导致骨质疏松症并成为癌症诱导的骨丢失的基础。我们认为，基因驱动巨噬细胞多核化也控制信号通路，这是必不可少的正常骨转换和炎症反应，但在骨质疏松症和慢性肉芽肿性疾病失调。在这个项目中，我们将研究健康和疾病中控制巨噬细胞多核化的分子机制。我们之前已经描述了一个涉及巨噬细胞多核化（MMnet）的134个基因的网络，现在将使用基于细胞培养的筛选方法鉴定对巨噬细胞多核化影响最大的10个基因。接下来，我们将通过分析通用基因缺失的影响来确定它们对骨骼和免疫系统的生理重要性。将根据其新颖性、效应大小、功能、实验易处理性和与人类疾病的相关性选择两个基因进行详细研究，其中将在巨噬细胞中特异性地删除基因。使用已建立的疾病激发模型的研究将确定巨噬细胞中两种基因的缺失是否可以防止骨质疏松症和慢性炎症性疾病的发展。这些研究将确定在肉芽肿疾病的发展和进展中发挥重要作用的信号通路，并提供对健康和疾病中巨噬细胞生物学的新理解。

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.