The P2X7 receptor for ATP as a therapeutic target in the prevention of radiation-induced salivary gland dysfunction

ATP 的 P2X7 受体作为预防辐射引起的唾液腺功能障碍的治疗靶点

• 批准号: 10659723
• 负责人: GARY Andrew WEISMAN
• 金额: $ 52.42万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659723
• 关键词: Acceleration; Acute; Adenosine; Antitumor Response; Apoptosis; CASP3 gene; Cations; Cells; Chronic; Cytoplasm; Cytoskeleton; Dental caries; Dinoprostone; Dose; Epithelium; Exhibits; Functional disorder; Genetic; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; Human Cell Line; Immune; Individual; Inflammasome; Inflammatory; Interleukin-1 beta; Ionizing radiation; Kinetics; Knowledge; Malnutrition; Mediating; Morphology; Mucositis; Mus; Normal tissue morphology; Nucleotides; Output; Patients; Prevention; Production; Purinergic P1 Receptors; Quality of life; Radiation; Radiation Protection; Radiation therapy; Radiation-Induced Cancer; Radiation-Protective Agents; Reactive Oxygen Species; Receptor Activation; Regimen; Salivary; Salivary Glands; Sialadenitis; Signal Transduction; Site; Technology; Testing; Therapeutic; Time; Tissues; Translating; Translations; Treatment Protocols; Xerostomia; antagonist; cancer therapy; cell injury; cell type; extracellular; head and neck cancer patient; in vivo; innovation; irradiation; mouse model; mouth squamous cell carcinoma; neoplastic cell; novel; novel strategies; nucleotide receptor; pharmacologic; preservation; prevent; radioprotected; receptor; response; targeted treatment; therapeutic target; transcriptome; transcriptomics; tripolyphosphate; tumor; tumor growth

Summary Despite technological advancements in head and neck squamous cell carcinoma (HNSCC) radiotherapies, collateral damage to surrounding normal tissues such as salivary glands following ionizing radiation (IR) remains a significant problem for these patients and severely diminishes their quality of life. It is estimated that >95% of HNSCC patients exhibit xerostomia and salivary gland hypofunction following the irradiation regimen and >73% of these patients continue to suffer for months to years after completion of radiotherapy. The lack of treatment options to prevent IR-induced xerostomia or recover salivary function is compounded by a limited understanding of the underlying mechanisms that mediate chronic IR-induced salivary dysfunction. Our previous studies demonstrate the action of extracellular ATP (eATP), a key “alarmin” molecule in damaged tissue that contributes to IR-induced salivary dysfunction, can be inhibited by pharmacological or genetic blockade of P2X7Rs for eATP, thereby conferring significant radioprotection to salivary glands. In addition, our studies show that radioprotection from P2X7R antagonism maintains normal salivary output through day 30 post-IR, although longer time periods relevant to the treatment of IR-induced chronic xerostomia and salivary dysfunction have not been investigated. Our ultimate goal is to use P2X7R antagonists as radioprotective agents to retain salivary gland function in head and neck cancer patients undergoing radiotherapy, although there is little information available on whether P2X7R antagonists will interfere with tumor regression achieved by radiotherapy, and proposed studies will address this gap in knowledge. The overall goal of this proposal is to develop an approach using P2X7R antagonism to prevent IR-induced salivary dysfunction in head and neck cancer patients receiving radiotherapy without inhibiting the IR-induced regression of HNSCC tumors. Successful completion of this proposal will greatly accelerate translation of this novel pharmacological approach to human patients undergoing IR therapies for head and neck cancer. The following specific aims will be pursued: Specific Aim 1 will develop a radioprotective approach using P2X7R antagonism in an irradiated syngeneic mouse model of HNSCC that preserves salivary gland function and anti-tumor responses. Specific Aim 2 will investigate the durability of the radioprotective effects of P2X7R antagonism towards developing an approach for chronic salivary dysfunction that occurs in HNSCC patients following radiotherapy. Specific Aim 3 will evaluate the contribution of eATP release and purinomic signaling downstream of P2X7R activation to IR-induced salivary gland dysfunction in mouse and human salivary gland organotypic cultures towards identifying alternative radioprotective targets and translating findings in mice to humans.

概括 尽管头颈鳞状细胞癌（HNSCC）放射治疗技术取得了进步， 电离辐射 (IR) 后对周围正常组织（例如唾液腺）的附带损害仍然存在 对这些患者来说这是一个重大问题，并且严重降低了他们的生活质量，据估计超过 95% 的患者。 HNSCC 患者在照射方案后出现口干和唾液腺功能减退，并且 >73% 这些患者在完成放射治疗后仍持续数月至数年缺乏治疗。 由于了解有限，预防红外线引起的口干症或恢复唾液功能的选择变得更加复杂 我们之前的研究揭示了介导慢性 IR 诱导的唾液功能障碍的潜在机制。 证明细胞外 ATP (eATP) 的作用，这是受损组织中的一种关键“警报”分子，有助于 IR 诱导的唾液功能障碍，可以通过药物或基因阻断 P2X7Rs 的 eATP 来抑制， 赋予唾液腺显着的辐射防护作用此外，我们的研究表明辐射防护作用。 P2X7R 拮抗作用在 IR 后第 30 天维持正常唾液分泌，尽管时间较长 尚未研究与治疗 IR 引起的慢性口干症和唾液功能障碍相关的药物。 我们的最终目标是使用 P2X7R 拮抗剂作为放射防护剂以保留头部唾液腺功能 和接受放射治疗的颈部癌症患者，尽管目前关于是否可以接受放射治疗的信息很少 P2X7R 拮抗剂会干扰放疗实现的肿瘤消退，拟议的研究将 该提案的总体目标是开发一种使用 P2X7R 的方法来解决这一知识差距。 拮抗作用可预防接受放射治疗的头颈癌患者中 IR 引起的唾液功能障碍 在不抑制 IR 诱导的 HNSCC 肿瘤消退的情况下，该提案的成功完成将极大地促进其发展。 加速将这种新颖的药理学方法转化为接受 IR 治疗的人类患者 头颈癌的具体目标如下： 具体目标 1 将开发一种在辐照同基因中使用 P2X7R 拮抗作用的辐射防护方法 保留唾液腺功能和抗肿瘤反应的 HNSCC 小鼠模型。 具体目标 2 将研究 P2X7R 拮抗作用的辐射防护作用的持久性 开发一种治疗 HNSCC 患者放疗后出现的慢性唾液功能障碍的方法。 具体目标 3 将评估 eATP 释放和 P2X7R 下游嘌呤组信号传导的贡献 在小鼠和人类唾液腺器官型培养物中激活红外线诱导的唾液腺功能障碍 替代辐射防护目标并确定小鼠和人类的发现。