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.

摘要 风湿性关节炎（RA）是一种自身免疫性疾病，其特征是严重的关节疼痛， 使人虚弱的炎性发作目前还没有安全有效的治疗方法， 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正常人的两倍。 非风湿性关节炎疼痛患者。适应不良的免疫细胞功能是RA的根本原因， 导致关节炎症和伤害感受器感觉神经元的激活，从而引发疼痛。 反过来，伤害感受器可以通过外周囊泡释放来调节组织中的免疫应答。 没有感觉神经支配的关节可以免受关节炎的影响，这强调了 感觉神经元控制疼痛和炎症。因此，神经免疫轴是 一个很好的治疗RA的潜在途径。然而，我们对各种感官的理解 关节中的神经元和免疫细胞，它们是如何相互作用的，以及这些细胞是如何相互作用的。 在RA过程中的相互作用变化是有限的。这是一个五年研究计划， 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。在为期两年的指导阶段，我将绘制受体-配体相互作用 在健康和炎症的感觉神经元和免疫细胞之间， 关节，以确定与关节炎相关的神经免疫通路，并确定哪些神经元 在关节炎中对免疫配体的反应驱动疼痛。我将通过利用创新的 构建受体-配体细胞-细胞相互作用组的方法， 机器学习并以空间和时间控制的方式抑制伤害感受器活动。 这种科学的培训将补充职业发展活动，以提高我的 科学沟通、领导、指导和科学行为道德方面的技能。的 在这次培训中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的慢性化。本研究 将揭示关节炎症的生物学机制，并指导新的 神经免疫疗法我召集了一群多才多艺的 导师谁将确保我接受广泛的培训，在疼痛神经生物学和 评价小鼠的感觉神经元功能。我的训练将进一步加强， 哈佛医学院和波士顿儿童医院独特的科学环境 研究社区，这是面向统一我在免疫学和感官专业知识 神经科学和使我成功地过渡到一个独立的学术地位，作为一个 疼痛研究员