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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘