Evaluation of TRPM8-expressing neurons as novel regulators of acute radiotherapy-associated pain in patients with head and neck cancer

评估表达 TRPM8 的神经元作为头颈癌患者急性放疗相关疼痛的新调节因子

• 批准号: 10361425
• 负责人: Michael Warren Nolan
• 金额: $ 34.78万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10361425
• 关键词: Action Potentials; Acute; Address; Adult; Afferent Neurons; American; Analgesics; Anatomy; Animals; Binding; Brain; Cancer Survivor; Caring; Cell Culture Techniques; Cells; Chronic; Constipation; Data; Development; Diagnosis; Epithelial; Evaluation; Exhibits; Face; Family; Family member; Generations; Glossitis; Goals; Grant; Head and Neck Cancer; Human; In Vitro; Inflammation; Ion Channel; Knockout Mice; Knowledge; Label; Lead; Malignant Neoplasms; Measures; Mediating; Methods; Molecular; Mus; NCAM1 gene; Nerve; Nerve Endings; Neurons; Operative Surgical Procedures; Opiate Addiction; Opioid; Oral; Oral cavity; Oral mucous membrane structure; Overdose; Pain; Pain management; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharyngeal structure; Production; Quality of life; Radiation; Radiation therapy; Reporting; Research; Risk; Role; Sampling; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Somatosensory Cortex; Spinal Cord; Stimulus; Testing; Therapeutic; Tissues; Tongue; Transgenic Organisms; Trigeminal System; Trigeminal nerve structure; Up-Regulation; Vascular Smooth Muscle; Work; addiction; alertness; antagonist; chemotherapy; experience; experimental study; glial cell-line derived neurotrophic factor; head and neck cancer patient; healing; improved; in vivo; injured; innovation; irradiation; keratinocyte; malignant mouth neoplasm; mouse model; neural circuit; neutralizing antibody; new therapeutic target; non-opioid analgesic; novel; novel therapeutics; opioid abuse; opioid therapy; opioid use; oral mucositis; orofacial; overexpression; pain behavior; pain relief; pain sensation; pain signal; prescription opioid; prevent; receptor; recruit; response; side effect

The goal of this proposal is to define the role of each component of the ARTN/GFR3/TRPM8 signaling pathway in radiation-associated pain (RAP). A common consequence of radiotherapy for head and neck cancer (HNC) is acute orofacial RAP. This pain is often severe, and difficult to control with current analgesics. Control of RAP relies on opioids in >80% of these cases. These drugs are not fully effective in most patients, and 6 months after finishing radiotherapy, one-third of HNC patients will still be opioid-dependent. There is an urgent need to identify safer, more effective, and less addictive pain relief strategies for HNC patients undergoing therapeutic irradiation. Addressing this need is prevented by a critical gap in our knowledge: the molecular and cellular mechanisms that drive acute orofacial RAP are unknown. In a mouse model of RAP, our preliminary data have indicated that a critical component of acute orofacial RAP is a signaling pathway which is usually identified as a “cold pain” pathway. The hypothesis to be tested in this proposal is that locally irradiated tissues generate extreme pain via a neural circuit that involves the “cold pain” pathway. This signaling pathway is principally mediated by neurons which express a specific ion channel called TRPM8. A typical mechanism for TRPM8 activation involves release of artemin (ARTN) from injured tissues; ARTN binds its neuronal receptor, called GFRα3, which in turn activates TRPM8. The objectives of this grant are: (1) to define the role of TRPM8 in mediating acute orofacial RAP; and (2) to determine whether ARTN/GFRα3 signaling is required for RAP signaling. We will test the hypothesis and achieve our objectives with three specific aims (SA): (SA1) to determine whether TRPM8-expressing neurons are critical to development of acute orofacial RAP; (SA2) to determine whether the GFRα3 receptor activates TRPM8 signaling in RAP; and (SA3) to determine whether ARTN is a critical activator of TRPM8 (and acute RAP) after oral irradiation. This contribution is significant because it will advance our understanding of the molecular and cellular mechanisms that drive acute orofacial RAP. The results will lay the groundwork for identification of new targeted treatments that will both improve comfort and reduce opioid-dependency for HNC patients with RAP. Importantly, if this RAP pathway is conserved between various anatomic sites, our results may extend well beyond the realm of HNC, and positively impact the analgesic options for patients who undergo radiotherapy for a wide range of cancers. The proposed research is innovative: there has been no research on the molecular and cellular mechanisms of RAP, and rather than attempting to alleviate pain by mitigating inflammation, we will identify strategies for direct inhibition of RAP. Our approach uses sophisticated methods for tracing neural circuits, and translational relevance is maximized through use of in vivo mouse studies, in vitro human cell culture experiments, and examination of patient-derived samples. Regardless of whether each component of our proposed mechanism fits together into a signaling cascade exactly as proposed, our work will generate novel, relevant information that advances the field toward novel therapies for acute orofacial RAP.

该提案的目的是定义ARTN/GFR3/TRPM8信号通路的每个组件的作用 在辐射相关疼痛（RAP）中。放射疗法的头颈癌（HNC）的常见结果是 急性口语说唱。这种疼痛通常很严重，并且很难用当前的镇痛药控制。控制说唱 在这些病例中> 80％的阿片类药物依赖于阿片类药物。这些药物在大多数患者中都不完全有效，六个月后 修饰放射疗法，HNC患者中有三分之一仍将取决于阿片类药物。迫切需要识别 对于接受治疗辐射的HNC患者，更安全，更有效，减少添加性疼痛策略。 在我们的知识上，临界差距阻止了解决这一需求：分子和细胞机制 那个驱动急性口语说唱是未知的。在RAP的鼠标模型中，我们的初步数据表明 急性口语RAP的关键成分是一种信号通路，通常被视为“冷痛” 路径。该提议中要检验的假设是，局部受辐照的组织通过 涉及“冷痛”途径的神经元电路。该信号通路主要由神经元介导 表达一个称为TRPM8的特定离子通道。 TRPM8激活的典型机制涉及释放 受伤组织的Artemin（Artn）； ARTN结合其神经元受体，称为GFRα3，进而激活 TRPM8。该赠款的目标是：（1）定义TRPM8在介导急性口语说唱中的作用；和 （2）确定RAP信号是否需要ARTN/GFRα3信号传导。我们将检验假设和 通过三个特定目标（SA）实现我们的目标：（SA1）确定表达TRPM8的神经元是否 对于急性口语说唱的发展至关重要； （SA2）确定GFRα3受体是否激活 RAP中的TRPM8信令； （SA3）确定ARTN是否是TRPM8的关键激活剂（急性 口头照射后。这项贡献很重要，因为它将促进我们对 驱动急性口语说唱的分子和细胞机制。结果将为 识别新的目标治疗方法，这些治疗将改善舒适性并减少HNC的阿片类药物依赖性 说唱患者。重要的是，如果此RAP途径在各个解剖站点之间配置，则我们的结果 可能会远远超出HNC的范围，并对接受的患者产生积极影响 用于广泛癌症的放射疗法。拟议的研究是创新的：没有关于 说唱的分子和细胞机制，而不是试图通过缓解疼痛来减轻疼痛 炎症，我们将确定直接抑制说唱的策略。我们的方法使用复杂的方法 用于追踪神经元电路，并通过体内小鼠研究最大化转化相关性，体外 人类细胞培养实验和患者衍生样品的检查。不管每个人是否是否 我们提出的机制的组成部分完全按照提出的方式拟合到信号级联反应中，我们的工作将会 生成新颖的相关信息，将领域迈向急性口语说唱的新疗法。