Glycolytic Reprogramming and Metformin as Therapeutics for Radiation-Induced Salivary Gland Dysfunction

预计2020年美国将新增超过53,000例头颈癌病例 包括放射治疗在内的治疗标准。虽然对治疗癌症有效，但辐射会导致 对周围唾液腺造成不可逆转的损害，导致功能丧失(即慢性唾液腺功能减退)。 吸痰功能减退的治疗方案只能提供症状控制，不能恢复唾液的产生 内生性的。因此，调节唾液腺功能障碍的潜在机制如下 需要了解放射治疗以实现恢复唾液腺功能的长期目标 放射治疗。众所周知，代偿性细胞增殖是辐射损伤反应的一部分。 这与唾液腺功能减退有关。糖酵解已被确定为推动代谢的一条途径 伤口愈合模型中的补偿性增殖和糖酵解抑制已被证明是成功的 减轻病理损伤，但这一途径尚未在辐射诱导的背景下进行研究 唾液腺功能障碍。二甲双胍是一种常见的抗糖尿病药物，它可以减少肿瘤细胞中的细胞增殖。 初步数据显示，二甲双胍可以恢复放射治疗后小鼠的唾液分泌，但 其在唾液腺中的作用机制尚未阐明。这项提案的目标是全面识别 辐射对唾液腺糖酵解的影响，以确定糖酵解抑制是否是潜在的 恢复放射后唾液产生的治疗靶点，并评价其作用机制 二甲双胍在这一途径上的治疗。我们假设辐射会增加唾液腺中的糖酵解。 糖酵解抑制会增加辐射后唾液的产生，而二甲双胍则会减少 放射治疗后糖酵解。为了测试这一点，我们将全面测量唾液上皮细胞中的糖酵解。 在辐射后的急性和慢性时间点，糖酵解后将测量唾液的产生 体内辐射暴露后的抑制作用，将其与未经处理和照射的对照组进行比较。糖酵解 放射和二甲双胍治疗后唾液上皮细胞的活性也将得到评估。这个 该项目的成果将对唾液上皮细胞糖酵解重新编程提供一个公正的理解 辐射损伤后的细胞，并将评估二甲双胍治疗领先的下游机制 在受损后恢复唾液腺功能。这可能会影响唾液腺研究以外的领域，如 这些结果可能扩展到其他类型的组织损伤。这项建议将作为私人投资计划的一部分 在她追求学术生涯的同时，她获得了博士学位论文。私家侦探将发展她的技术、指导和 在Kirsten Limesand博士、Floyd Chilton博士和Megha Padi博士的实验室工作时的协作技能 和亚利桑那大学研究I机构的其他学生。介绍并发布调查结果 从这项提议将建立PI的沟通技能，因为她追求自己的职业生涯作为学术研究员。

Over 53,000 new cases of head and neck cancer are projected for 2020 in the United States with the standard of treatment involving radiation therapy. Although effective for treating cancer, radiation causes irreversible damage to surrounding salivary glands, resulting in loss of function (i.e. chronic hyposalivation). Treatment options for hyposalivation only provide symptom control and do not restore the production of saliva endogenously. Therefore, the underlying mechanisms regulating salivary gland dysfunction following radiotherapy need to be understood to achieve the long-term goal of restoring salivary gland function following radiotherapy. It is well-established that compensatory cell proliferation is part of the radiation damage response that is correlated with salivary gland hypofunction. Glycolysis has been identified as a metabolic pathway driving compensatory proliferation in wound healing models and glycolytic inhibition has demonstrated success for attenuating pathological injury, but this pathway has not been investigated in the context of radiation-induced salivary gland dysfunction. Metformin, a common anti-diabetic drug, decreases cell proliferation in tumor cells. Preliminary data shows metformin restores saliva production in mice following radiation treatment, yet the mechanism in the salivary gland has not been elucidated. The goal of this proposal is to comprehensively identify the effect of radiation on glycolysis in the salivary gland, to determine if glycolytic inhibition is a potential therapeutic target for restoring saliva production following radiation, and to evaluate the mechanistic effect of metformin treatment on this pathway. We hypothesize that radiation increases glycolysis in the salivary gland and that glycolytic inhibition will increase saliva production following radiation, and that metformin decreases glycolysis post radiotherapy. To test this, glycolysis will be comprehensively measured in salivary epithelial cells at acute and chronic timepoints following radiation and saliva production will be measured following glycolytic inhibition after radiation exposure in vivo, which will be compared to untreated and irradiated controls. Glycolytic activity will also be evaluated in salivary epithelial cells following radiation and metformin treatment. The outcomes of this project will provide an unbiased understanding of glycolytic reprogramming in salivary epithelial cells following radiation damage and will evaluate the downstream mechanism of metformin treatment leading to restored salivary gland function following damage. This may impact fields beyond salivary gland research, as these results may be expandable to other types of tissue damage. This proposal will serve as part of the PI’s doctoral dissertation as she pursues a career in academia. The PI will develop her technical, mentoring, and collaborative skills as she works in the laboratories of Drs. Kirsten Limesand, Floyd Chilton, and Megha Padi with other students at a Research I institution, the University of Arizona. Presenting and publishing the findings from this proposal will build the PI’s communication skills as she pursues her career as an academic researcher.