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

放射治疗是一种挽救生命的治疗头颈部癌症。虽然放射疗法通常能成功治疗癌症，但严重的副作用是损害肿瘤附近的健康组织，包括唾液腺。这种组织损伤导致唾液产生能力降低（一种称为慢性口干或口干的疾病），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，放射治疗的副作用对患者的生活质量产生不利影响。现有的慢性口干的治疗方法（例如唾液替代品和漱口水）只能提供短期缓解，因此需要开发更好，更有效的治疗方法。放疗后唾液腺会随着时间的推移而退化。然而，为什么会发生这种情况目前尚不清楚。在这项提案中，我们将首先使用从小鼠和人类分离的腺体，广泛地描述放射治疗后唾液腺中发生的情况。我们已经知道，巨噬细胞，一种长期以来被认为是许多不同器官修复和再生的关键参与者的细胞，对于放射治疗后的唾液腺再生至关重要，如果没有它们，就不会发生有效的再生。相反，随着时间的推移，巨噬细胞在放疗后丢失，这表明支持巨噬细胞的东西丢失了。我们知道唾液腺巨噬细胞依赖于一种名为集落刺激因子-1（CSF 1）的因子，并且CSF 1在放疗后下降，但我们不知道唾液腺中的哪些细胞产生CSF 1。在这里，我们将使用基因改变的小鼠来消耗特定细胞中的CSF 1，并探索对巨噬细胞的影响。最后，我们将评估我们是否可以通过用CSF 1治疗或通过将新的巨噬细胞移植到唾液腺中来挽救放疗后的唾液腺功能。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，以及我们是否可以最终挽救放疗损伤。

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.