Radiation-induced Salivary Gland Vascular Injury: Mechanisms and Interventions

项目摘要 放射性口腔干燥症（RIX）是头部放疗最常见和最持久的晚期副作用， 颈部癌症患者，导致言语受损，进食和吞咽困难， 降低患者的生活质量。可悲的是，没有明确的治疗或有效的缓解策略， RIX的常规临床管理。制定安全有效的战略来减轻RIX已经成为一项重要的任务。 由于有限的机械洞察力和缺乏客观的方法来描述正常的 组织损伤在这方面，我们的临床前研究表明，辐射的时间演变- 诱导的血管损伤和DNA损伤反应受宿主免疫状态的影响。我们的初步 研究还表明，维生素D（VitD）缺乏会加重辐射诱导的血管损伤， vivo.相反，VitD治疗保护唾液腺免受3D类器官的辐射损伤。这些 观察沿着已知的维生素D的抗炎和抗氧化作用使我们假设 通过饮食或给予活性代谢物骨化三醇纠正VitD缺乏症，可以保护 唾液腺免受辐射损伤并减轻体内RIX。为了验证这些假设，我们建议 描述唾液腺血管分布和免疫谱的动态变化， 在小鼠中进行放射治疗（目的1）并评估VitD对预防/减轻RIX的影响（目的2）。临床前 一项大型动物试验，以检查维生素D对头颈部肿瘤和唾液腺对 还提出了体积调制弧治疗（目标3）。使用新的实验模型和成像 技术，应用程序将系统地检查血管和免疫机制的基础 唾液腺放射损伤和定义的治疗潜力的维生素D作为一种放射防护剂。的 拟议的研究将使维生素D补充方案的发展，以预防RIX在头部和 癌症患者在不久的将来。

Project Summary Radiation-induced xerostomia (RIX) is the most frequent and permanent late side-effect of RT in head and neck cancer patients that leads to compromised speech, difficulty in eating and swallowing and an overall reduction in quality of life in patients. Sadly, no definitive therapy or effective mitigating strategy is available for routine clinical management of RIX. The development of safe and effective strategies to mitigate RIX has been hindered by limited mechanistic insight and lack of objective methods to characterize the trajectory of normal tissue injury. In this regard, our preclinical studies have revealed that the temporal evolution of radiation- induced vascular injury and DNA damage response is influenced by the host immune status. Our preliminary studies have also revealed that vitamin D (VitD) deficiency exacerbates radiation-induced vascular injury in vivo. Conversely, VitD treatment protects salivary glands from radiation injury in 3D organoids. These observations along with the known anti-inflammatory and antioxidant effects of VitD have led us to hypothesize that correction of VitD deficiency through diet or administration of the active metabolite, calcitriol, can protect salivary glands from radiation damage and alleviate RIX in vivo. To test these hypotheses, we propose to characterize the dynamic changes in vascularity and immune profiles of salivary glands in response to radiotherapy in mice (Aim 1) and evaluate the impact of VitD on preventing/mitigating RIX (Aim 2). A preclinical large animal trial to examine the effects of VitD on response of head and neck tumors and salivary glands to volumetric modulated arc therapy is also proposed (Aim 3). Using novel experimental models and imaging technologies, the application will systematically examine the vascular and immune mechanisms underlying salivary gland radiation injury and define the therapeutic potential of VitD as a radioprotective agent. The proposed studies will enable development of VitD supplementation regimens for prevention of RIX in head and neck cancer patients in the near future.