Ineffective wound healing responses enable chronic radiation-induced salivary gland dysfunction

摘要： 超过73%的头颈部癌症患者继续遭受 放疗结束后几个月到几年出现口干症，这使这一疾病成为最引人注目的 唾液腺生物学中的问题。尽管癌症治疗方面的技术进步，但抵押品 唾液腺的损害对这些患者来说仍然是一个严重的问题，并严重减少 他们的生活质量。辐射引起的唾液腺损伤领域严重受阻于 缺乏一个全面的模型来详细说明损伤的分子阶段。总体愿景是 通过确定唾液的愈合阶段来恢复放疗后患者的唾液腺功能 导致对其分期的精确治疗的分层和管理的腺体。这 提案将使用涉及炎症的伤口愈合的顺序阶段来解决和 通过上皮组织的增殖和分化来重建组织的步骤 实现这一愿景。我们假设受辐射的唾液腺不能有效地进展 通过伤口愈合阶段导致长时间的功能障碍。我们之前的工作已经证明 辐射诱导唾液腺的增殖部分是由于pkcζ顶端的破坏。 极性复合体导致YAP核局部化增强，而恢复唾液的模型 功能上修复了YAP的心尖极性，减少了核的定位。我们建议开发 一个集成了伤口愈合的每个阶段的模型，详细说明了阶段和阶段之间的相互作用 核YAP对这些阶段进展的影响。这项工作的成果 包括：1)调节持续YAP核转位的输入；2)慢性核YAP对 防止IR后的再分化，3)当/如果需要YAP来恢复唾液腺功能时， 4)揭示了阻止唾液腺恢复的伤口愈合阶段之间的相互作用 功能。了解这一过程将产生积极的影响，因为它揭示了以下干预点 促进唾液腺功能的恢复。

Abstract: More than 73% of head and neck cancer patients continue to suffer from the chronic consequences of xerostomia months to years after the completion of radiotherapy making this one of the most compelling issues in salivary gland biology. Despite technological advancements in cancer therapies, collateral damage to salivary glands remains a significant problem for these patients and severely diminishes their quality of life. The field of radiation-induced salivary gland damage is severely hampered by the lack of a comprehensive model detailing the molecular stages of damage. The overall vision is to restore salivary gland function in patients following radiotherapy by identifying healing stages in salivary glands that lead to the stratification and administration of precise therapeutics for their stage. This proposal will use the sequential phases of wound healing involving inflammation to its resolution and reconstitution of tissue through proliferation and differentiation of epithelial tissue as steps to accomplish this vision. We hypothesize that irradiated salivary glands fail to efficiently progress through the wound healing phases leading to prolonged dysfunction. Our prior work has demonstrated that radiation-induced proliferation in salivary glands is due in part to disruption of the PKCζ apical polarity complex leading to enhanced nuclear localization of Yap, while models that restore salivary function have repaired apical polarity and reduced nuclear localization of Yap. We propose to develop a model that integrates each phase of wound healing detailing the interactions between phases and the impact of nuclear Yap on the progression through these phases. The outcomes from this work include: 1) inputs regulating sustained Yap nuclear translocation, 2) ability of chronic nuclear Yap to prevent re-differentiation after IR, 3) when/if Yap is necessary for restoration of salivary gland function, 4) uncovering the interplay between wound healing phases that prevent restoration of salivary gland function. Understanding this process would have a positive impact by revealing intervention points that promote restoration of salivary gland function.