Neuro-immune modulation of pain in health and disease

健康和疾病中疼痛的神经免疫调节

• 批准号: 10522386
• 负责人: Christopher Ryan Donnelly
• 金额: $ 61.69万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522386
• 关键词: Absence of pain sensation; Address; Afferent Neurons; Agonist; Analgesics; Behavioral; Biochemical; Bioinformatics; Biological Response Modifiers; Cancer Patient; Cells; Clinical Trials; Communication; Data; Deglutition; Dendritic Cells; Disease; Eating; Electrophysiology (science); Genetic; Genetic Transcription; Goals; Gold; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Health; Homeostasis; Human; Immune; Immunooncology; Immunotherapeutic agent; Immunotherapy; Interferon Type I; Interferons; Knowledge; Lead; Malignant Neoplasms; Mediating; Molecular; Morbidity - disease rate; Mus; Neuroimmune; Neurons; Nociception; Nociceptors; Oral cavity; Organism; Oropharyngeal; Pain; Pain management; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Physiological; Property; Publications; Quality of life; Reporting; Research Personnel; Role; STING agonists; Shapes; Signal Transduction; Stimulus; TRPV1 gene; Techniques; Testing; Therapeutic; Translations; Tumor Immunity; base; behavioral phenotyping; cancer immunotherapy; cancer pain; cancer subtypes; cancer therapy; cancer type; cell type; combinatorial; cytokine; debilitating pain; experience; experimental study; feeding; functional disability; mortality; mouse model; neuronal cell body; nonhuman primate; novel; novel strategies; novel therapeutics; pain inhibition; pain model; pain relief; sensor; small molecule; standard care; standard of care; success; translational potential; tumor; tumor-immune system interactions

Project Summary: The majority of patients with advanced stage cancers experience moderate to severe pain, and more than half of all cancer patients report insufficient pain relief by the currently available therapeutics. Head and neck squamous cell carcinomas (HNSCC) involving the oral cavity and/or oropharynx are regarded as a particularly painful cancer type which produces coincident functional impairments that lead to difficulties in feeding, swallowing, and communication. These functional impairments substantially reduce quality of life for cancer patients and are associated with increased morbidity and mortality. Thus, there is a critical need for novel therapeutics that are capable of providing safe and effective pain relief. Moreover, any newly emerging pain therapeutic must be compatible with existing and emerging standard of care cancer treatments, such as cancer immunotherapy, which has emerged as the gold-standard treatment for many cancer subtypes over the last decade. We recently discovered that pain-sensing peripheral sensory neurons (nociceptors) express the innate immune regulator STING. Strikingly, activation of STING can produce antinociception in mice and non-human primates, both in steady-state conditions and in pathological pain states. This is noteworthy, as small molecule STING agonists have shown remarkable efficacy in promoting antitumor immunity and are currently being explored as cancer therapeutics in clinical trials. The objective of this proposal is to identify the cellular and molecular mechanisms by which STING regulates nociception, both in steady-state conditions and in HNSCC pain models. We hypothesize that STING dynamically regulates nociception in steady-state and disease conditions through a mechanism dependent on nociceptor-immune cell signaling and its subcellular localization. In Specific Aim 1, we will determine how STING signaling in peripheral sensory neurons, TRPV1+ nociceptors, and classical type-1 dendritic cells (cDC1s) each contribute to STING-mediated antinociception in health and disease, using syngeneic cancer pain models, conditional genetics, behavioral phenotyping, immune profiling, and biochemical and immunohistochemical approaches. In Specific Aim 2, we will determine how the subcellular localization of STING influences its molecular and physiological properties to influence nociception and antitumor immunity. Overall, completion of these experiments will substantiate STING as a unique “neuro-immunotherapy” target capable of conferring combinatorial analgesia and antitumor properties, a finding of immediate translational relevance given the paucity of options available to patients suffering from cancer pain.

项目概要： 大多数晚期癌症患者都会经历中度至重度疼痛，超过一半的患者会经历中度至重度疼痛。 的所有癌症患者报告目前可用的治疗方法不足以缓解头颈部疼痛。 口腔和/或口咽部的鳞状细胞癌（HNSCC）被认为是特别常见的癌症。 痛苦的癌症类型，会产生同时的功能障碍，导致喂养困难， 这些功能障碍大大降低了癌症患者的生活质量。 患者并与发病率和死亡率增加有关，因此迫切需要新的药物。 此外，能够安全有效地缓解任何新出现的疼痛的疗法。 必须与现有和新兴的癌症治疗护理标准兼容，例如癌症 免疫疗法，在过去已成为许多癌症亚型的金标准治疗 我们最近发现感知疼痛的外周感觉神经元（伤害感受器）表达先天的感觉。 免疫调节剂 STING 引人注目的是，STING 的激活可以在小鼠和非人类体内产生反作用。 灵长类动物，无论是在稳态条件下还是在病理疼痛状态下，作为小分子，这一点都是值得注意的。 STING激动剂在促进抗肿瘤免疫方面表现出显着功效，目前正在研究中 在临床试验中探索癌症治疗方法该提案的目的是确定细胞和癌症治疗方法。 STING 在稳态条件下和 HNSCC 中调节伤害感受的分子机制 我们认为 STING 动态调节稳态和疾病中的伤害感受。 通过依赖于伤害感受器免疫细胞信号传导及其亚细胞的机制来调节条件 在具体目标 1 中，我们将确定外周感觉神经元 TRPV1+ 中的 STING 信号传导如何进行。 伤害感受器和经典 1 型树突状细胞 (cDC1) 各自有助于 STING 介导的抗伤害感受 健康和疾病，使用同基因癌症疼痛模型、条件遗传学、行为表型， 在具体目标 2 中，我们将确定免疫分析、生化和免疫组织化学方法。 STING 的亚细胞定位如何影响其分子和生理特性 总体而言，这些实验的完成将证实 STING 是一种有效的治疗方法。 独特的“神经免疫疗法”目标能够赋予组合镇痛和抗肿瘤特性， 鉴于患有以下疾病的患者可用的选择很少，这一发现具有直接的转化相关性 癌症疼痛。