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.

文摘:

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.