Autophagy & Functional Restoration of Irradiated Salivary Glands

描述（由申请人提供）：该申请涉及广泛的挑战领域（15）转化科学和特定的挑战主题，15- de -104唾液腺功能恢复。正常的唾液腺功能对口腔健康至关重要。头颈部癌症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，最常见的是口干症。随之而来的唾液腺功能减退导致显著的发病率，降低了抗癌治疗的有效性，降低了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，这仍然是一个主要的治疗挑战。我们研究的主要目的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。自噬是一种基本的细胞分解代谢降解过程，细胞蛋白质和细胞器被吞噬，通过溶酶体消化并循环利用。根据细胞环境的不同，自噬可以影响促生存或促死亡的结果。自噬相关基因Atg5在自噬过程中起着不可或缺的作用。我们得到了Atg5f/f；Aqp5-Cre转基因小鼠，其中Aquaporin-5 （Aqp5）驱动的Cre重组酶通过特异性切除唾液腺泡细胞中Atg5的柔化外显子3来破坏自噬。我们建议研究自噬对放射后唾液腺泡细胞命运的影响，并利用FDA批准的自噬激活剂雷帕霉素或自噬抑制剂氯喹在唾液功能恢复模型中发挥作用。我们的中心假设是：1)适当的自噬激活对于清除受损的腺泡和导管细胞内受损的细胞器/蛋白质以及照射后的整个细胞尸体非常重要；2)通过自噬及时有效地清除照射后的细胞尸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了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治疗的可行性，以恢复数千名已经完成抗癌治疗但仍然遭受唾液腺功能减退副作用的头颈癌患者的唾液腺功能。本申请涉及广泛的挑战领域（15）转化科学和特定的挑战主题，15- de -104唾液腺功能恢复。正常的唾液腺功能对口腔健康至关重要。头颈部癌症的放射治疗通常会引起严重的继发性副作用，影响正常的唾液腺功能。这一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，以恢复数千名已经完成抗癌治疗但仍然遭受唾液腺功能减退副作用的头颈癌患者的唾液腺功能。

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.