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会经历中度至重度疼痛，超过一半的患者会出现疼痛。 的癌症患者报告目前可用的治疗剂不足以缓解疼痛。头颈 涉及口腔和/或口咽的鳞状细胞癌（HNSCC）被认为是一种特别常见的恶性肿瘤。 疼痛性癌症类型，其产生导致进食困难的并发功能障碍， 吞咽和交流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，对小说的需求非常迫切。 能够提供安全有效的疼痛缓解的治疗剂。此外，任何新出现的疼痛 治疗剂必须与现有的和新兴的护理癌症治疗标准相容，例如癌症 免疫疗法，过去几年已成为许多癌症亚型的金标准治疗方法 十年我们最近发现，感受疼痛的外周感觉神经元（伤害感受器）表达先天性的 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中产生抗伤害感受。 灵长类动物，无论是在稳态条件和病理性疼痛状态。这是值得注意的，因为小分子 STING激动剂在促进抗肿瘤免疫中显示出显著的功效，并且目前正在研究中。 在临床试验中作为癌症治疗剂进行探索。该提案的目的是识别蜂窝和 STING在稳态条件下和HNSCC中调节伤害感受的分子机制 疼痛模型我们假设STING在稳态和疾病状态下动态调节伤害感受， 通过依赖于伤害感受器-免疫细胞信号传导及其亚细胞 本地化在具体目标1中，我们将确定外周感觉神经元中的STING信号，TRPV 1 + 伤害感受器和经典的1型树突状细胞（cDC 1）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， 免疫分析以及生物化学和免疫组织化学方法。在具体目标2中，我们将确定 STING的亚细胞定位如何影响其分子和生理特性， 伤害感受和抗肿瘤免疫。总的来说，这些实验的完成将证实STING是一种 独特的“神经免疫治疗”靶点，能够赋予组合镇痛和抗肿瘤特性， 考虑到患有以下疾病的患者缺乏选择， 癌症疼痛。