Novel models to study dorsal root ganglion neurons in knee osteoarthritis pain

研究膝骨关节炎疼痛中背根神经节神经元的新模型

• 批准号: 10783393
• 负责人: Chelsie L Brewer
• 金额: $ 24.59万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10783393
• 关键词: Ablation; Addictive Analgesics; Adult; Affect; Age; Analgesics; Anterior Cruciate Ligament; Arthritis; Automobile Driving; Basic Science; Behavioral; Behavioral Assay; Blood - brain barrier anatomy; Cell Culture Techniques; Cells; Central Nervous System; Chemosensitization; Chronic; Clinical; Clinical Pathology; Coculture Techniques; Dangerousness; Data; Degenerative polyarthritis; Dependence; Disease; Doctor of Philosophy; Electrophysiology (science); Environment; Excitatory Synapse; Fiber; Functional disorder; Gene Expression; Genes; Genetic; Genetic Recombination; Goals; Headache; Health; Helping to End Addiction Long-term; Human; Image; Immobilization; Inflammatory; Injections; Injury; Investigation; Ion Channel; Joints; Knee; Knee Osteoarthritis; Knee joint; Medial meniscus structure; Mediating; Membrane; Mental Depression; Mentors; Methods; Mission; Modeling; Mus; National Institute of Arthritis, and Musculoskeletal, and Skin Diseases; Nerve; Nerve Regeneration; Nervous System; Neurons; Neuropathy; Nociception; Non-Steroidal Anti-Inflammatory Agents; Occupations; Operative Surgical Procedures; Opioid; Pain; Pain Disorder; Pain Research; Pathologic; Pathway interactions; Patients; Peripheral Nerves; Persons; Pharmacologic Substance; Phase; Population; Post-Procedural Pain; Postoperative Pain; Procedures; Proprioception; Quality of life; Replacement Arthroplasty; Research; Rodent; Signal Transduction; Sleeplessness; Source; Spinal; Spinal Cord; Spinal Ganglia; Swelling; System; TRPV1 gene; Techniques; Testing; Therapeutic; Tissues; Training; Translations; Traumatic Arthropathy; Universities; Vertebral column; Viral; Work; alternative treatment; capsaicin receptor; career development; chronic pain; chronic painful condition; clinically relevant; common treatment; disability; experience; high risk; human model; human tissue; joint inflammation; joint injury; knee pain; knee replacement arthroplasty; mouse model; neural circuit; novel; osteoarthritis pain; pain relief; pain-related disability; pre-clinical; preservation; prevent; programs; side effect; single-cell RNA sequencing; success; therapeutic target; tissue culture; transcriptome; transcriptomics; transmission process

PROJECT SUMMARY/ABSTRACT Knee osteoarthritis (OA) is a leading source of disabling pain, affecting nearly 20% of US adults over 45, which will only increase as our population ages. Although remarkable research and clinical efforts are being poured into discovering vital disease-modifying treatments (i.e., reversing joint damage, joint replacement), therapeutics targeting pain caused by knee OA are lacking. Given the high burden of pain in this disorder (e.g., sleeplessness, immobility, depression), and the fact that current treatments are invasive, lack long-term efficacy, carry high risk of severe side effects, and are inconsistent as analgesics (e.g., knee replacement, nerve ablation, and opioids)—adequate pain therapeutics are urgently needed. Peripheral nerves or dorsal root ganglion (DRG) are generally the first neurons to transmit pain, thus targeting DRG can prevent aberrant pain from initiating a nervous system cascade resulting in chronic, maladaptive changes to neural circuits. Furthermore, DRG are located outside of the blood brain barrier, providing an easily accessible therapeutic target. However, it is important to precisely target DRG populations transmitting knee OA pain, to preserve beneficial populations like those responsible for knee proprioception and stabilization. Relatedly, recent clinical gains have been made by precisely targeting specific functional alterations in DRG during pain states caused by small fiber neuropathy and postoperative pain. Additionally, the basic science pain research field has suffered from a lack of translation from commonly used models to clinical pathologies, but exciting advances are being made by applying basic science approaches in relevant mediums like human tissues. Here I propose that identifying the DRG populations driving knee OA-induced changes in nociceptive neural circuits in addition to identifying the OA-induced alterations within these DRG populations, will provide avenues for potential therapeutics. In the mentored K99 phase, my mentor Julie Kauer, PhD, and my advisors Stuart Goodman, MD, PhD, Gregory Corder, PhD, Elizabeth Serafin, MS, and Lu Chen, PhD, will support my career development and training. Building upon my current work demonstrating that the TRPV1- expressing DRG population drives inflammatory injury-mediated spinal potentiation, 1) I will determine if knee OA initiates spinal potentiation via TRPV1-expressing DRG neurons innervating the knee. Additionally, 2) I will profile DRG neurons active in knee OA pain using the TRAP (Transient Recombination in Active Populations) technique in combination with behavioral assays, transcriptomic analysis, and electrophysiology. Finally, in the independent phase 3) I will use a co-culture system with human-derived DRG neurons and knee tissue recovered from arthroplasties to investigate the genetic, population-level activity, and functional changes within DRG neurons in an osteoarthritic joint environment. This will generate leads to build upon in my future research program and generate fundable projects for a multiyear investigation of knee OA pain.

项目概要/摘要 膝骨关节炎 (OA) 是致残性疼痛的主要原因，影响着近 20% 的 45 岁以上的美国成年人， 随着我们的人口老龄化，只会增加。尽管正在投入大量的研究和临床努力 发现重要的疾病缓解疗法（即逆转关节损伤、关节置换）， 目前缺乏针对膝关节 OA 引起的疼痛的治疗方法。鉴于这种疾病带来的沉重疼痛负担（例如， 失眠、不动、抑郁），而且目前的治疗方法是侵入性的，缺乏长期效果 功效，具有严重副作用的高风险，并且与镇痛药不一致（例如膝关节置换术、 神经消融和阿片类药物）——迫切需要足够的疼痛治疗方法。周围神经或背根 神经节（DRG）通常是最先传递疼痛的神经元，因此针对 DRG 可以预防异常疼痛 启动神经系统级联反应，导致神经回路发生慢性、适应不良的变化。 此外，DRG 位于血脑屏障之外，提供了一种易于获得的治疗方法 目标。然而，重要的是精确定位传播膝关节 OA 疼痛的 DRG 人群，以保持 有益人群，例如负责膝关节本体感觉和稳定的人群。相关地，近期临床 通过在疼痛状态期间精确针对 DRG 的特定功能改变取得了成果 由小纤维神经病变和术后疼痛引起。此外，基础科学疼痛研究领域还有 缺乏从常用模型到临床病理学的转化，但取得了令人兴奋的进展 是通过在人体组织等相关介质中应用基础科学方法来制造的。在这里我 提出识别驱动膝关节 OA 诱导的伤害性神经变化的 DRG 群体 除了识别这些 DRG 群体中 OA 引起的改变之外，电路还将提供 潜在治疗的途径。在指导的 K99 阶段，我的导师 Julie Kauer 博士和我的 顾问 Stuart Goodman（医学博士、博士）、Gregory Corder（博士）、Elizabeth Serafin（硕士）和 Lu Chen（博士）将 支持我的职业发展和培训。以我目前的工作为基础，证明 TRPV1- 表达 DRG 群体驱动炎症损伤介导的脊髓增强，1）我将确定膝关节是否 OA 通过支配膝关节的表达 TRPV1 的 DRG 神经元启动脊髓增强。另外，2）我会 使用 TRAP（活跃群体中的瞬时重组）分析在膝关节 OA 疼痛中活跃的 DRG 神经元 技术与行为测定、转录组分析和电生理学相结合。最后，在 独立阶段3）我将使用人源DRG神经元和膝关节组织的共培养系统 从关节置换术中恢复来研究其遗传、群体水平活动和功能变化 骨关节炎关节环境中的 DRG 神经元。这将为我的未来提供线索 研究计划并为膝关节骨关节炎疼痛的多年研究产生可资助的项目。