Elucidating the neuroimmune mechanisms underlying pain and inflammation in autoimmune arthritis

阐明自身免疫性关节炎疼痛和炎症的神经免疫机制

• 批准号: 10784407
• 负责人: Aakanksha Jain
• 金额: $ 24.05万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10784407
• 关键词: Acute; Address; Advisory Committees; Afferent Neurons; Arthralgia; Arthritis; Attenuated; Autoimmune Diseases; Autoimmunity; Behavior; Biological; Boston; Calcium; Cell physiology; Cells; Chronic; Clinical; Communication; Communities; Complement; Data; Denervation; Development; Disease remission; Ensure; Environment; Ethics; Five-Year Plans; Flare; Foundations; Future; Gene Expression; Generations; Hypersensitivity; Image; Immune; Immune response; Immunologic Receptors; Immunology; Inflammation; Inflammatory; Investigation; Joints; Leadership; Ligands; Light; Link; Machine Learning; Maintenance; Maps; Measures; Mediating; Mentors; Mentorship; Methodology; Modeling; Molecular; Mus; Myeloid Cells; Neurobiology; Neuroimmune; Neuroimmunomodulation; Neuromodulator; Neurons; Neuropeptides; Nociceptors; Opioid; Pain; Pain Measurement; Pathology; Pathway interactions; Patients; Pediatric Hospitals; Peripheral; Phase; Positioning Attribute; Postdoctoral Fellow; Recurrence; Recurrent disease; Recurrent pain; Regulation; Relapse; Research; Research Personnel; Resolution; Rheumatoid Arthritis; Role; Sensory; Skin injury; Spinal Ganglia; Synovial Membrane; System; T-Lymphocyte; Testing; Tetanus Toxin; Tissues; Training; Viral; Work; arthritic pain; autoimmune arthritis; autoimmune inflammation; career; career development; cell type; computerized tools; cytokine; effective therapy; effector T cell; experimental study; inflammatory pain; innovation; insight; ion channel blocker; joint inflammation; medical schools; mouse model; nerve supply; neuroimmunology; novel; novel therapeutics; opioid use; opioid user; pain behavior; pain patient; prevent; programs; receptor; response; sensory neuroscience; single-cell RNA sequencing; skills; somatosensory; tissue resident memory T cell; tool; transcriptomics; vesicular release

Abstract Rheumatoid arthritis (RA) is an autoimmune disease characterized by severe joint pain and debilitating inflammatory flares. There are currently no safe and effective treatments that achieve long-term remission, and therefore, RA patients are twice as likely to become chronic opioid users than non-RA pain patients. Maladaptive immune cell function is the underlying cause of RA which leads to joint inflammation and activation of nociceptor sensory neurons that trigger pain. Nociceptors, in turn, can regulate immune responses in tissues via peripheral vesicle release. Joints without sensory innervation are protected from arthritis, underscoring the key role of sensory neurons in controlling both pain and inflammation. Therefore, the neuroimmune axis is an excellent potential avenue, to treat RA. However, our understanding of the diverse sensory neurons and immune cells in the joints, how they interact with each other, and how these interactions change over the course of RA is limited. This proposal is a five-year plan of research, training, and career development focused on studying the role of neuroimmune interactions in RA pain and inflammation. In the two-year mentored phase, I will map the receptor-ligand interactions between sensory neurons and immune cells at a single-cell resolution in healthy and inflamed joints to identify neuroimmune pathways linked to arthritis, and also determine which neurons drive pain in response to immune ligands in arthritis. I will accomplish this by utilizing innovative approaches to construct receptor-ligand cell-cell interactomes, assess pain behavior in mice using machine learning and inhibit nociceptor activity in a spatially and temporally controlled manner. This scientific training will complement the career development activities selected to enhance my skills in scientific communication, leadership, mentorship, and ethics of scientific conduct. The insights and skills gained during this training will guide my research in the independent phase, elucidating how nociceptor-immune interactions contribute to the chronicity of RA. This research will uncover the biological mechanisms of joint inflammation and guide the development of novel neuroimmune-based therapies. I have assembled a diverse group of highly accomplished mentors who will ensure that I receive extensive training in pain neurobiology and in the assessment of sensory neuronal function in mice. My training will be further enhanced by the unique scientific environment of the Harvard Medical School and Boston Children’s Hospital research community, which is geared towards unifying my expertise in immunology and sensory neuroscience and enabling my successful transition into an independent academic position as a pain researcher.

抽象的 类风湿关节炎（RA）是一种自身免疫性疾病，其特征是严重的关节疼痛和 衰弱的炎症耀斑。当前没有安全有效的治疗方法可以实现 长期缓解，因此，RA患者成为慢性阿片类药物使用者的可能性是 比非RA疼痛患者。适应性免疫细胞功能是RA的根本原因 导致触发疼痛的伤害感受器感觉神经元的关节感染和激活。 反过来，伤害感受器可以通过外围囊泡释放来调节组织中的免疫回报。 没有感觉神经神经的关节受到关节炎的保护，强调了 控制疼痛和炎症的感觉神经元。因此，神经免疫轴为 治疗RA的极佳潜在途径。但是，我们对潜水员感官的理解 关节中的神经元和免疫细胞，它们如何相互作用以及如何相互作用 在RA过程中的互动变化是有限的。该建议是一项五年研究计划， 培训和职业发展的重点是研究神经免疫相互作用在RA中的作用 疼痛和炎症。在两年的阶段，我将映射接收器配体相互作用 在健康和发炎的单细胞分辨率下，感觉神经元和免疫细胞之间 关节以识别与关节炎相关的神经免疫途径，并确定哪些神经元 响应关节炎中的免疫配体驱动疼痛。我将使用创新来实现这一目标 构建受体配体细胞 - 细胞相互作用的方法，使用小鼠的疼痛行为 机器学习并以空间和临时控制的方式抑制伤害感受器的活性。 这种科学培训将完成选出的职业发展活动，以增强我的 科学沟通，领导力，精神训练和科学行为道德的技能。 在此培训期间获得的见解和技能将指导我在独立阶段的研究， 阐明伤害感受器 - 免疫相互作用如何促进RA的慢性性。这项研究 将发现关节感染的生物学机制，并指导新颖的发展 基于神经免疫性的疗法。我聚集了一群高度成就的群体 将确保我接受疼痛神经生物学的广泛培训的导师和 评估小鼠的感觉神经元功能。我的培训将通过 哈佛医学院和波士顿儿童医院的独特科学环境 研究社区，旨在统一我的免疫学和感官方面的专业知识 神经科学并使我成功地过渡到独立的学术地位 疼痛研究员。