Metabolic dysregulation during radiation-induced salivary gland dysfunction

辐射引起的唾液腺功能障碍期间的代谢失调

• 批准号: 10254415
• 负责人: KIRSTEN H LIMESAND
• 金额: $ 19.19万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-04 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10254415
• 关键词: 6-Phosphofructokinase; Acute; Affect; Animal Model; Antioxidants; Apical; Area; Biochemical Pathway; Bioinformatics; Biological Markers; Biological Specimen Banks; Biology; Biopsy; Cell physiology; Cells; Chronic; Citric Acid Cycle; Clinical; Complex; Conflict (Psychology); DNA Repair; Data; Defect; Disease; Effectiveness; Enzymes; Foundations; Functional disorder; Genetic Transcription; Genus Hippocampus; Goals; Head and Neck Cancer; Homeostasis; Intervention; Kinetics; Knowledge; Lead; Macronutrients Nutrition; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Nuclear; Outcome; Oxygen Consumption; Pathway Analysis; Pathway interactions; Patients; Pentosephosphate Pathway; Phase; Phenotype; Problem Solving; Process; Quality of life; Radiation; Radiation therapy; Reaction; Regulation; Reporting; Research Personnel; Saliva; Salivary Gland Tissue; Salivary Glands; Serum; Stratification; Technology; Therapeutic; Therapeutic Intervention; Time; Tissues; Transcription Coactivator; Urine; Vision; Work; Xerostomia; aminoacid biosynthesis; cancer therapy; common treatment; experimental study; extracellular; functional loss; head and neck cancer patient; healing; lipid metabolism; loss of function; metabolic phenotype; metabolomics; multidisciplinary; novel; novel therapeutic intervention; novel therapeutics; nucleotide metabolism; patient stratification; preference; radiation effect; radiation response; repaired; response; restoration; saliva sample; salivary acinar cell; side effect; skills; stressor; therapeutically effective; transcriptomics

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 (long-term goal) 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 integrate metabolic changes at three time points of radiation-induced dysfunction that build a mechanistic foundation to bridge to clinical therapeutic interventions. We hypothesize that changes in salivary gland metabolism enable the loss of function phenotype following radiation treatment of salivary glands. The outcomes from this work include: 1) Metabolic networks that are kinetically altered following IR, 2) Identification of novel regulators of the metabolic phenotype following IR, 3) Linkage of changes in metabolic networks with cellular mechanisms that are involved in the response of salivary glands to IR damage. Understanding this process would have a positive impact by revealing intervention points that promote restoration of salivary gland function.

摘要： 超过73%的头颈部癌症患者继续遭受口干症的慢性后果 放疗结束后数月至数年，使其成为唾液中最引人注目的问题之一。 腺体生物学尽管癌症治疗的技术进步，唾液腺的附带损害 对这些患者来说仍然是一个严重的问题，并严重降低了他们的生活质量。辐射场- 诱导的唾液腺损伤严重阻碍了缺乏一个全面的模型，详细说明 损伤的分子阶段总体愿景（长期目标）是恢复患者的唾液腺功能 在放射治疗后，通过确定导致分层的唾液腺愈合阶段， 给予针对其阶段的精确治疗。该提案将在三个时间点整合代谢变化 辐射引起的功能障碍，建立一个机制基础，以桥梁临床治疗 干预措施。我们假设唾液腺代谢的变化使功能表型丧失 唾液腺的放射治疗后。这项工作的成果包括：1）代谢网络 IR后发生动力学改变，2）IR后代谢表型的新型调节剂的鉴定 IR，3）代谢网络中的变化与参与免疫应答的细胞机制的联系。 唾液腺受到红外线损伤。了解这一过程将通过揭示干预措施产生积极影响 促进唾液腺功能恢复的穴位。