Exploring the role of macrophage-niche crosstalk in radiation-induced salivary gland degeneration

放射治疗是头颈癌患者的救命疗法。虽然放射治疗在治疗癌症方面通常很成功，但严重的副作用是损害肿瘤附近的健康组织，包括唾液腺。这种组织损伤会导致分泌唾液的能力下降（一种被称为慢性口干或口干症的情况），从而导致进食、说话和睡眠困难，并有窒息的风险。此外，它还会导致蛀牙和口腔健康问题。因此，放射治疗的副作用会对患者的生活质量产生不利影响。现有的慢性口干治疗方法（如唾液替代品和漱口水）只能短期缓解，因此需要开发更好、更有效的治疗方法。放射治疗后唾液腺随时间退化。然而，为什么会发生这种情况目前尚不清楚。在这个提议中，我们将首先广泛地描述放射治疗后唾液腺发生的情况，使用从小鼠和人类分离的腺体。我们已经知道巨噬细胞，一种长期以来被认为在许多不同器官的修复和再生中起关键作用的细胞，是放射治疗后唾液腺再生所必需的，没有巨噬细胞就不会发生有效的再生。相反，随着时间的推移，放疗后巨噬细胞会消失，这表明支持巨噬细胞的某种物质丢失了。我们知道唾液腺巨噬细胞依赖于一种叫做集落刺激因子-1 （CSF1）的因子，而CSF1在放疗后会下降，但我们不知道唾液腺中的哪些细胞会产生CSF1。在这里，我们将使用转基因小鼠来消耗特定细胞中的CSF1，并探索对巨噬细胞的影响。最后，我们将评估放射治疗后是否可以通过CSF1治疗或移植新的巨噬细胞到唾液腺中来恢复唾液腺功能。总的来说，这将告诉我们应该关注哪些细胞以获得更好的再生，以及我们最终是否可以挽救放疗损伤。

Radiotherapy is a life-saving treatment for those with head and neck cancer. Although radiotherapy is very often successful in treating the cancer, a serious side-effect is damage to healthy tissue near the tumour(s), including the salivary glands. This tissue damage results in a reduced ability to produce saliva (a condition known as chronic dry mouth or xerostomia), which leads to difficulties with eating, speaking and sleeping and a risk of choking. Furthermore, it causes tooth decay and oral health problems. Thus, the side-effects of radiotherapy adversely affect a patient's quality of life. Existing treatments for chronic dry mouth (e.g. saliva substitutes and mouthwashes) only give short-term relief and therefore there is a need to develop better, more effective treatments. The salivary glands degenerate over time following radiotherapy. However, why this happens is currently unknown. In this proposal we will first extensively profile what happens in the salivary gland after radiotherapy, using glands isolated from both mice and humans. We already know that macrophages, a cell that has long been considered a key player in the repair and regeneration of many different organs, are essential for salivary gland regeneration after radiotherapy, and in their absence efficient regeneration does not occur. Conversely, over time macrophages are lost after radiotherapy, suggesting that something that supports the macrophages is missing. We know that salivary gland macrophages rely on a factor called Colony-Stimulating-Factor-1 (CSF1) and that CSF1 declines after radiotherapy, but we do not know which cells in the salivary gland produce CSF1. Here we will use genetically altered mice to deplete CSF1 in specific cells and explore the effect on macrophages. Finally, we will assess if we can rescue salivary gland function after radiotherapy by treating with CSF1 or by transplanting new macrophages into the salivary glands. Collectively, this will tell us which cells we should be focussing on to get better regeneration and whether we can ultimately rescue radiotherapy injury.