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

预计2020年美国将有超过53，000例头颈癌新发病例 放射治疗的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损伤，导致功能丧失（即慢性唾液分泌不足）。 唾液分泌不足的治疗方案只能提供症状控制，不能恢复唾液的产生 内生的因此，调节以下唾液腺功能障碍的潜在机制 放疗需要被理解，以实现恢复唾液腺功能的长期目标， 放疗众所周知，补偿性细胞增殖是辐射损伤反应的一部分 与唾液腺功能减退有关糖酵解已被确定为一种代谢途径， 在伤口愈合模型中的代偿性增殖和糖酵解抑制已经证明了对于 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，可降低肿瘤细胞的细胞增殖。 初步数据显示，二甲双胍在放射治疗后恢复了小鼠的唾液分泌， 唾液腺中的作用机制尚未阐明。该提案的目标是全面查明 辐射对唾液腺糖酵解的影响，以确定糖酵解抑制是否是一种潜在的 治疗靶点，用于在辐射后恢复唾液产生，并评估 二甲双胍治疗对这一途径的影响。我们假设辐射增加了唾液腺的糖酵解 糖酵解抑制会增加辐射后的唾液分泌，二甲双胍会减少 放疗后糖酵解。为了验证这一点，将在唾液上皮细胞中全面测量糖酵解 在辐射后的急性和慢性时间点， 体内辐射暴露后的抑制，将其与未处理和辐射对照进行比较。糖解 还将在放射和二甲双胍治疗后的唾液上皮细胞中评价活性。的 本项目的结果将提供一个无偏见的了解糖酵解重编程在唾液腺上皮细胞 细胞辐射损伤，并将评估二甲双胍治疗的下游机制， 修复受损后的唾液腺功能这可能会影响唾液腺研究以外的领域， 这些结果可以扩展到其它类型的组织损伤。该提案将作为PI的一部分， 她在学术界追求职业生涯时发表了博士论文。PI将发展其技术、指导和 她在Kirsten Limesand、弗洛伊德Chilton和Megha Padi博士的实验室工作时， 和其他学生在亚利桑那大学的一个研究机构。介绍和公布调查结果 从这个建议将建立PI的沟通技巧，她追求她的职业生涯作为一个学术研究。

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.