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

无效的伤口愈合反应会导致慢性辐射引起的唾液腺功能障碍

• 批准号: 10678634
• 负责人: KIRSTEN H LIMESAND
• 金额: $ 34.71万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10678634
• 关键词: Acute; Address; Apical; Biology; Biopsy; Cells; Chronic; Clinic; Clinical; Complex; Cues; Data; Defect; Detection; Effectiveness; Epithelium; Equilibrium; Failure; Functional disorder; Genetically Engineered Mouse; Gland; Goals; Head and Neck Cancer; Inflammation; Inflammatory; Intervention; Literature; Macrophage; Mediator; Modeling; Molecular; Natural regeneration; Nuclear; Nuclear Translocation; Outcome; Pathway interactions; Patients; Phase; Phenotype; Physiological; Play; Population Heterogeneity; Pre-Clinical Model; Process; Production; Proliferating; Quality of life; Radiation; Radiation induced damage; Radiation therapy; Regulation; Resolution; Role; Saliva; Salivary; Salivary Glands; Sampling; Series; Signal Induction; Stratification; Technology; Testing; Therapeutic; Time; Tissues; Transcription Coactivator; Undifferentiated; Validation; Vision; Work; Wound models; Xerostomia; cancer therapy; cell type; chronic wound; common treatment; cytokine; head and neck cancer patient; healing; mouse model; novel therapeutics; pharmacologic; pre-clinical; prevent; reconstitution; repaired; response; restoration; side effect; standard of care; stem cells; wound healing

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.

抽象的： 超过73％的头颈癌患者继续遭受慢性后果 放射治疗完成后的几个月至几年，这是最引人注目的 唾液腺生物学问题。尽管癌症疗法的技术进步，但 唾液腺损害仍然是这些患者的重大问题，并且严重减少 他们的生活质量。辐射引起的唾液腺损伤的领域严重阻碍了 缺乏详细介绍损害分子阶段的全面模型。总体愿景是 通过鉴定唾液的愈合阶段，在放疗后恢复患者的唾液腺功能 导致其阶段精确治疗的分层和给药的腺体。这 提案将使用伤口愈合参与注入的顺序阶段，以解决其分辨率和 通过增生和上皮组织的分化来重建组织的步骤 实现这一愿景。我们假设受照射的唾液腺无法有效进步 通过伤口愈合阶段导致长时间功能障碍。我们先前的工作已经证明 辐射诱导的唾液腺增殖部分是由于PKCζ顶的破坏 极性复合物导致YAP的核定位增强，而恢复唾液的模型 功能已经修复了根尖极性并减少了YAP的核定位。我们建议发展 整合伤口愈合的每个阶段的模型，详细介绍了阶段之间的相互作用 核YAP对通过这些阶段进展的影响。这项工作的结果 包括：1）调节持续YAP核易位的输入，2）慢性核YAP的能力 防止IR后重新分化，3）/如果需要YAP恢复唾液腺功能时， 4）发现伤口愈合阶段之间的相互作用，以防止唾液腺恢复 功能。理解这一过程将通过揭示干预点会产生积极影响 促进唾液腺功能的恢复。

项目成果

Evaluating the transcriptional landscape and cell-cell communication networks in chronically irradiated parotid glands.

• DOI: 10.1016/j.isci.2023.106660
• 发表时间: 2023-05-19
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Rheinheimer, Brenna A.;Pasquale, Mary C.;Limesand, Kirsten H.;Hoffman, Matthew P.;Chibly, Alejandro M.
• 通讯作者: Chibly, Alejandro M.