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

烟酰胺单核苷酸（NMN）作为治疗口腔粘膜炎的新疗法

• 批准号: 9770831
• 负责人: DAVID A. SINCLAIR
• 金额: $ 21.19万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9770831
• 关键词: 3-Dimensional; Acute; Analgesics; Animals; Anti-inflammatory; Antiinflammatory Effect; Apoptosis; Apoptotic; Attenuated; Basal Cell; Biological Assay; Cancer Patient; Cell Culture Techniques; Cell physiology; Cells; Cellular Morphology; Cheek structure; Clinical Paths; DNA Damage; DNA Repair Enzymes; Development; Enzymes; Epithelial; Epithelium; Gastrointestinal tract structure; Gold; Hamsters; Head and Neck Cancer; Health; Hematopoietic Stem Cell Transplantation; Human; In Vitro; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Isotope Labeling; Lead; Maintenance; Measures; Mediating; Medical Research; Metabolic; Mitochondria; Modeling; Molecular; Morphology; Mucositis; Mucous Membrane; Mus; Nicotinamide Mononucleotide; Nicotinamide adenine dinucleotide; Oral; Oral Pathology; Oral cavity; Oral mucous membrane structure; Outcome; Patients; Poly(ADP-ribose) Polymerases; Quality of life; Radiation; Radiation therapy; Reactive Oxygen Species; Resolution; Role; SIRT1 gene; Secondary to; Severities; Signaling Protein; Sirtuins; Stratum Basale; Study models; Supportive care; Testing; Tissues; Toxic effect; Treatment Efficacy; Ulcer; Whole-Body Irradiation; antimicrobial; cancer therapy; chemoradiation; chemotherapeutic agent; chemotherapy; cost; cytotoxicity; disabling symptom; dosage; effective therapy; experimental study; gastrointestinal; gastrointestinal epithelium; histological stains; improved; in vivo; inhibitor/antagonist; irradiation; knock-down; novel; novel therapeutics; oral mucositis; outcome forecast; prevent; regenerative; response; secondary infection; senescence; side effect

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.

概括 尽管靶向化疗药物的开发取得了进展，但继发于口腔粘膜炎 传统化疗和放疗仍然是最常见的相关毒性之一 与癌症治疗。它会导致代价高昂且令人衰弱的症状，在严重的情况下，会导致病情恶化 患者的预后。高达 100% 的头颈癌病例会出现口腔粘膜炎，而 60-90% 的病例会出现口腔粘膜炎 造血干细胞移植病例数。常规化疗引起的急性DNA损伤 辐射会导致一组称为聚 ADP 核糖的 DNA 修复酶快速过度激活 利用烟酰胺腺嘌呤二核苷酸 (NAD+) 作为共底物的聚合酶 (PARP)。的耗尽 NAD+ 导致 SIRT1 活性降低，SIRT1 是一种 NAD+ 依赖性脱酰酶，可抑制 炎。在过去的几年中，NAD+前体已成为最令人兴奋的分子之一 医学研究。我们假设通过 NAD+ 治疗维持口腔粘膜中的 NAD+ 水平 前体烟酰胺单核苷酸（NMN）将大大减少炎症级联反应，并大大减少 减少口腔粘膜炎的严重程度和持续时间，为预防和治疗口腔粘膜炎提供了新途径 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 在体内的保护和抗炎作用。 体外口腔细胞并使用同位素标记的 NMN 追踪 NAD+ 的通量。在目标 2 中，我们将使用仓鼠 放射诱发的口腔粘膜炎模型，用于评估局部 NMN 是否可以延迟发作、降低峰值、 抑制粘膜炎的总体范围并促进其消退。在目标 3 中，我们将通过以下方式探索机制： NMN 通过测试 SIRT1 是否是口腔粘膜炎的关键调节因子（介导抗- NMN 的炎症活性。这些实验将系统地评估 NAD+ 前体是否 可以有效缓解口腔粘膜炎，并指导开发安全有效的治疗方法以减少口腔粘膜炎的发生。 降低美国癌症治疗费用，并显着提高癌症患者的生活质量。