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.

该提案的目标是定义 ARTN/GFRα3/TRPM8 信号通路各组成部分的作用 头颈癌 (HNC) 放射治疗的一个常见后果是放射相关疼痛 (RAP)。 急性口面部 RAP 疼痛通常很严重，并且用目前的 RAP 镇痛药难以控制。 其中超过 80% 的病例依赖阿片类药物，这些药物在大多数患者中并不完全有效，并且 6 个月后。 放疗结束后，三分之一的 HNC 患者仍存在阿片类药物依赖，迫切需要确定这一点。 为接受放射治疗的 HNC 患者提供更安全、更有效且不易成瘾的疼痛缓解策略。 我们知识中的一个关键差距阻碍了满足这一需求：分子和细胞机制 在 RAP 小鼠模型中，驱动急性口面部 RAP 的因素尚不清楚，我们的初步数据表明： 急性口面部 RAP 的一个关键组成部分是信号通路，通常被认为是“冷痛” 该提案要检验的假设是，局部受辐射的组织通过以下途径产生极度疼痛。 涉及“冷痛”通路的神经回路，该信号通路主要由神经元介导。 TRPM8 表达一种称为 TRPM8 的特定离子通道，TRPM8 激活的典型机制涉及释放。 来自受损组织的 artemin (ARTN) 与其神经元受体（称为 GFRα3）结合，进而激活 TRPM8。这项资助的目标是：(1) 定义 TRPM8 在介导急性口面部 RAP 中的作用； (2)确定RAP信号传导是否需要ARTN/GFRα3信号传导我们将检验假设和。 通过三个具体目标 (SA) 来实现我们的目标： (SA1) 确定 TRPM8 表达神经元是否 对于急性口面部 RAP 的发生至关重要；(SA2) 以确定 GFRα3 受体是否激活 RAP 中的 TRPM8 信号传导；和 (SA3) 以确定 ARTN 是否是 TRPM8 的关键激活剂（以及急性 口腔照射后的 RAP）这一贡献非常重要，因为它将增进我们对口腔照射的理解。 驱动急性口面部 RAP 的分子和细胞机制的结果将为该研究奠定基础。 确定新的靶向治疗方法，既可以提高 HNC 的舒适度，又可以减少对阿片类药物的依赖 重要的是，如果这个 RAP 通路在不同的解剖部位之间是保守的，我们的结果 可能会远远超出 HNC 的范围，并对接受治疗的患者的镇痛选择产生积极影响 拟议的研究具有创新性：目前还没有针对多种癌症的放射治疗。 RAP 的分子和细胞机制，而不是试图通过减轻疼痛来减轻疼痛 炎症，我们将确定直接抑制 RAP 的策略我们的方法使用复杂的方法。 用于追踪神经回路，并通过使用体内小鼠研究、体外研究来最大化翻译相关性 人类细胞培养实验，以及患者来源样本的检查，无论是否每个。 我们提出的机制的组成部分完全按照提议组合成信号级联，我们的工作将 产生新颖的相关信息，推动该领域朝着急性口面部 RAP 的新疗法发展。