Radiation-induced Salivary Gland Vascular Injury: Mechanisms and Interventions

辐射引起的唾液腺血管损伤：机制和干预措施

基本信息

批准号：
10701306
负责人：
Mukund Seshadri
金额：
$ 47.15万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-22 至 2024-09-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10701306
关键词：
3-Dimensional Acute Adverse effects Affect Anatomy Animals Anti-Inflammatory Agents Antioxidants Biological Markers Blood Vessels CD34 gene Calcitriol Cancer Patient Cells Chronic Clinical Clinical Management Collagen DNA Damage Deglutition Development Diet Dietary Administration Dietary Supplementation Eating Endothelium Evaluation Evolution Experimental Models Future Gland Goals HIF1A gene Head and Neck Cancer Head and Neck Neoplasms Head and Neck Squamous Cell Carcinoma Head and neck structure High Prevalence Histologic Image Imaging technology Immune Immune response Immunocompetent Injury Intervention Investigation Kinetics Lead Measurement Measures Mediating Metabolic Methods Modeling Mucous Membrane Multimodal Imaging Mus Normal tissue morphology Organoids Oryctolagus cuniculus Oxidative Stress Oxygen Consumption PECAM1 gene Patient Care Patients Pattern Phase Phenotype Pre-Clinical Model Predisposition Prevention Quality of life Radiation Radiation Injuries Radiation Protection Radiation induced damage Radiation therapy Radiation-Protective Agents Radiobiology Regimen Reporting Research Role Salivary Salivary Glands Severities Signal Transduction Speech Testing Therapeutic Therapeutic Effect Toxic effect Ultrasonography Vascular Endothelial Growth Factors Vascular resistance Vitamin D Vitamin D Deficiency Vitamin D supplementation Xerostomia cancer therapy experience head and neck cancer patient hemodynamics imaging modality immunological status in vivo insight mouse model novel oral infection pre-clinical preclinical evaluation preclinical study prevent radiation response response side effect standard of care tissue injury tool translational potential tumor vascular injury

项目摘要

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.

项目概要放射引起的口干症 (RIX) 是头部和颈部放疗最常见且永久的晚期副作用。颈癌患者会导致言语障碍、进食和吞咽困难以及整体症状患者生活质量下降。遗憾的是，目前还没有明确的治疗方法或有效的缓解策略 RIX 的常规临床管理。制定安全有效的策略来缓解 RIX 由于机械洞察力有限和缺乏客观方法来描述正常轨迹的阻碍组织损伤。在这方面，我们的临床前研究表明，辐射的时间演变- 引起的血管损伤和DNA损伤反应受到宿主免疫状态的影响。我们的初步研究还表明，维生素 D (VitD) 缺乏会加剧辐射引起的血管损伤体内。相反，VitD 治疗可以保护唾液腺免受 3D 类器官的辐射损伤。这些观察结果以及 VitD 已知的抗炎和抗氧化作用使我们做出假设通过饮食或服用活性代谢物骨化三醇纠正维生素D缺乏症可以保护唾液腺免受辐射损伤并减轻体内 RIX。为了检验这些假设，我们建议描述唾液腺血管分布和免疫特征的动态变化对小鼠进行放射治疗（目标 1）并评估 VitD 对预防/减轻 RIX 的影响（目标 2）。临床前大型动物试验，旨在检查 VitD 对头颈部肿瘤和唾液腺的反应的影响还提出了容积调节弧疗法（目标 3）。使用新颖的实验模型和成像技术，该应用程序将系统地检查潜在的血管和免疫机制唾液腺辐射损伤并确定了 VitD 作为辐射防护剂的治疗潜力。这拟议的研究将有助于开发 VitD 补充方案，以预防头部和颈部 RIX 近期颈癌患者。