Autophagy & Functional Restoration of Irradiated Salivary Glands

自噬

• 批准号: 7815595
• 负责人: David K Ann
• 金额: $ 44.53万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7815595
• 关键词: Acute; Address; Adverse effects; Affect; Apoptosis; Area; Autophagocytosis; Autophagosome; Biomedical Research; Cell Death; Cell Survival; Cell physiology; Cells; Cellular Stress; Cessation of life; Chloroquine; Chronic; Cytoprotection; Data; Deglutition; Deglutition Disorders; Digestion; Ductal Epithelial Cell; Eating; Effectiveness; Enhancers; Excision; Exons; Exposure to; FDA approved; Failure; Figs - dietary; Genes; Goals; Head and Neck Cancer; Head and neck structure; Homeostasis; Injury; Modeling; Morbidity - disease rate; Mus; Nature; Oral; Oral health; Organelles; Outcome; Pathway interactions; Patients; Phenotype; Physiological; Play; Process; Proteins; Quality of life; Radiation; Radiation induced damage; Radiation therapy; Recycling; Research; Role; Salivary; Salivary Glands; Sirolimus; Stimulus; Supporting Cell; Target Populations; Taste Perception; Testing; Therapeutic; Tissues; Transgenic Mice; Translational Research; Treatment Protocols; Xerostomia; aquaporin 5; base; cancer therapy; cell suicide; effective therapy; functional restoration; head and neck cancer patient; improved; in vivo; inhibitor/antagonist; innovation; insight; irradiation; mouse model; novel; oral infection; oral mucositis; pre-clinical; promoter; protein misfolding; protein structure; recombinase; research study; response; restoration; salivary acinar cell; small molecule; theories

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15-DE-104 Functional Restoration of Salivary Glands. Proper salivary gland function is critical for oral health. Radiation therapy for head and neck cancer often causes significant secondary side effects that impact normal salivary gland function, most commonly xerostomia. The ensuing salivary gland hypofunction results in significant morbidity, diminishes the effectiveness of anti-cancer therapies and decreases the quality of life for these patients. Current therapies are unable to permanently restore salivary function, which remains a major therapeutic challenge. The primary goal of our research is to elucidate the role of radiation-induced autophagy in salivary glands in response to irradiation. Secondarily, through the use of small molecule therapeutic approaches, we wish to investigate whether activation of autophagy leads to cytoprotection or exacerbation of radiation-induced injury to salivary tissues. Autophagy is a constitutive cellular catabolic degradation process whereby cellular proteins and organelles are engulfed, digested through the lysosomal machinery and recycled. Depending on the cellular context, autophagy can affect pro-survival or pro-death outcomes. The autophagy-related 5 gene, Atg5, has been established as an indispensable player in autophagy. We have generated Atg5f/f;Aqp5-Cre transgenic mice, in which the Aquaporin-5 (Aqp5)-driven Cre recombinase is targeted to impair autophagy by excising the floxed exon 3 of Atg5 specifically in salivary acinar cells. We propose to investigate the role of autophagy in influencing the fate of salivary acinar cells following radiation and to utilize the FDA approved autophagy activator rapamycin or autophagy inhibitor chloroquine in a restoration of salivary function model. Our central hypotheses are: 1) Appropriate activation of autophagy is important in the removal of damaged organelles/proteins within damaged acinar and ductal cells as well as whole cell corpses following irradiation, and 2) Timely and efficient removal of cell corpses following irradiation by autophagy will accelerate restoration of salivary function. The expected outcomes from these experiments will contribute substantially to our understanding on the role of autophagy in protecting salivary gland function against radiation-induced damage. In addition, they will provide a unique opportunity to evaluate the feasibility of autophagy-targeted therapies to restore salivary gland function in thousands of head and neck cancer patients that have completed anti-cancer therapies yet continue to suffer from the side effect of salivary gland hypofunction. This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15-DE-104 Functional Restoration of Salivary Glands. Proper salivary gland function is critical for oral health. Radiation therapy for head and neck cancer often causes significant secondary side effects that impact normal salivary gland function. This proposal will provide a unique opportunity to evaluate the feasibility of autophagy-targeted therapies to restore salivary gland function in thousands of head and neck cancer patients that have completed anti-cancer therapies yet continue to suffer from the side effect of salivary gland hypofunction.

描述(由申请人提供)：本申请涉及广泛的挑战领域(15)翻译科学和具体的挑战主题，15-DE-104唾液腺功能恢复。适当的唾液腺功能对口腔健康至关重要。头颈癌的放射治疗经常会引起严重的副作用，影响正常的唾液腺功能，最常见的是口干症。随之而来的唾液腺功能低下会导致严重的发病率，降低抗癌治疗的有效性，并降低这些患者的生活质量。目前的治疗方法无法永久恢复唾液功能，这仍然是治疗的主要挑战。我们研究的主要目标是阐明辐射诱导的唾液腺自噬在辐射反应中的作用。其次，通过使用小分子治疗方法，我们希望研究自噬的激活是否会导致细胞保护或加剧辐射引起的唾液组织损伤。自噬是一种结构性的细胞分解代谢过程，细胞蛋白质和细胞器被吞噬，通过溶酶体机器消化和循环。根据细胞环境的不同，自噬可以影响支持生存或支持死亡的结果。自噬相关基因ATG5在自噬过程中起着不可或缺的作用。我们已经建立了Atg5f/f；AQP5-Cre转基因小鼠，在其中，水通道蛋白-5(AQP5)驱动的Cre重组酶的靶向是通过在唾液腺泡细胞中特异地切除ATG5的外显子3来破坏自噬。我们建议研究自噬在影响放射后唾液腺泡细胞命运中的作用，并利用FDA批准的自噬激活剂雷帕霉素或自噬抑制剂氯喹来恢复唾液功能模型。我们的中心假设是：1)适当地激活自噬对于清除照射后受损的腺泡和导管细胞以及整个细胞身体中的受损细胞器/蛋白质是重要的；2)通过自噬及时有效地清除照射后的细胞身体将加速唾液功能的恢复。这些实验的预期结果将大大有助于我们理解自噬在保护唾液腺功能免受辐射损伤中的作用。此外，它们将提供一个独特的机会来评估自噬靶向疗法的可行性，以恢复数千名已完成抗癌治疗但仍受到唾液腺功能减退副作用的头颈癌患者的唾液腺功能。这项申请涉及广泛的挑战领域(15)翻译科学和具体的挑战主题，15-DE-104唾液腺的功能恢复。适当的唾液腺功能对口腔健康至关重要。头颈癌的放射治疗通常会引起严重的副作用，影响正常的唾液腺功能。这项提议将提供一个独特的机会来评估自噬靶向治疗的可行性，以恢复数千名已完成抗癌治疗但仍受到唾液腺功能低下副作用的头颈癌患者的唾液腺功能。