Nicotinamide Mononucleotide (NMN) as a Novel Therapeutic in the Treatment of Oral Mucositis

摘要 尽管靶向化疗药物的开发取得了进展，但口腔粘膜炎继发于 常规化疗和放射治疗仍然是最常见的毒性反应之一。 接受癌症治疗。它会导致昂贵和虚弱的症状，在严重的情况下，还会恶化 患者的预后。口腔粘膜炎发生在高达100%的头颈部癌症患者和60%-90%的患者中 造血干细胞移植的案例。常规化疗引起的急性DNA损伤 辐射会导致一组DNA修复酶--聚-ADP-核糖迅速过度激活 利用烟酰胺腺嘌呤二核苷酸(NAD+)作为共底物的聚合酶(PAP)。资源的枯竭 NAD+导致SIRT1活性降低，SIRT1是一种依赖NAD+的脱酰基酶，可抑制 发炎。在过去的几年里，NAD+前体已经成为最令人兴奋的分子之一 医学研究。我们假设用NAD+治疗可以维持口腔粘膜中的NAD+水平 前体烟酰胺单核苷酸(NMN)将大大减少炎症级联反应，并极大地 减少口腔粘膜炎的严重程度和持续时间，为预防和治疗提供了一条新的途径 使人虚弱的状况。为了验证这一假设，我们将进行体外和体内研究，模拟 口腔粘膜炎的病理学。在目标1中，我们将研究NMN对小鼠的保护和抗炎作用。 并用同位素标记的NMN示踪NAD+的流量。在目标2中，我们将利用一只仓鼠 放射性口腔粘膜炎模型评估局部应用NMN是否延迟发病，降低峰值， 抑制总的范围，促进粘膜炎的消退。在目标3中，我们将通过 哪种NMN通过检测SIRT1是否是口腔粘膜炎的关键调节因子来减轻粘膜炎 NMN的炎症活性。这些实验将系统地评估NAD+前体 可有效缓解口腔粘膜炎，指导制定安全有效的治疗方法，减少口腔粘膜炎的发生 降低美国癌症治疗成本，显著提高癌症患者的生活质量。

SUMMARY Despite advances in the development of targeted chemotherapeutic agents, oral mucositis secondary to conventional chemotherapy and radiation remains one of the most frequently encountered toxicities associated with cancer therapy. It leads to both costly and debilitating symptoms and, in severe cases, a worsened prognosis for the patient. Oral mucositis occurs in up to 100% of cases of head and neck cancer and 60 – 90% of cases of hematopoietic stem cell transplants. Acute DNA damage caused by conventional chemotherapy and radiation leads to rapid hyperactivation of a group of DNA-repairing enzymes known as poly-ADP-ribose polymerases (PARPs) that utilize nicotinamide adenine dinucleotide (NAD+) as a co-substrate. The depletion of NAD+ leads to a decrease in the activity of SIRT1, an NAD+-dependent deacylase that suppresses inflammation. In the past few years, NAD+ precursors have emerged as one of the most exciting molecules in medical research. We hypothesize that maintenance of NAD+ levels in oral mucosa by treatment with the NAD+ precursor nicotinamide mononucleotide (NMN) will greatly reduce the inflammatory cascade and greatly reduce the severity and duration of oral mucositis, providing a novel path to preventing and treating this debilitating condition. To test this hypothesis we will perform both in vitro and in vivo studies modeling the pathology of oral mucositis. In Aim 1, we will study the protective and anti-inflammatory effects of NMN in in vitro oral cells and trace the flux of NAD+ using isotopically labeled NMN. In Aim 2 we will utilize a hamster radiation-induced oral mucositis model to evaluate if topical NMN delays the onset, reduces the peak, dampens the total extent, and promotes resolution of mucositis. In Aim 3 we will explore the mechanisms by which NMN attenuates mucositis by testing if SIRT1 is a key regulator of oral mucositis that mediates the anti- inflammatory activities of NMN. These experiments will systematically evaluate whether an NAD+ precursor can effectively mitigate oral mucositis and guide the development of safe and effective treatments to cut the costs of cancer treatment in the US and significantly improve quality of life for cancer patients.