PHLPP inhibition and Osteoarthritis-Associated Pain

PHLPP 抑制和骨关节炎相关疼痛

基本信息

批准号：
10581073
负责人：
Nathan P Staff
金额：
$ 20.99万
依托单位：
MAYO CLINIC ROCHESTER
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：
2023-02-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10581073
关键词：
Afferent Neurons Animal Model Arthralgia Behavior Behavior Therapy Biological Assay Biological Models Cartilage Cells Chondrocytes Chronic Confocal Microscopy Data Degenerative polyarthritis Deterioration Development Disease Fibroblasts Goals Human Hypersensitivity Immobilization Immunohistochemistry In Vitro Induced pluripotent stem cell derived neurons Injections Injury Intra-Articular Injections Joints Knee Injuries Knowledge Laboratories Measures Medial meniscus structure Mitochondria Molecular Mouse Strains Mus Natural regeneration Nerve Fibers Neurites Neurons Neurotransmitters Nociception Operative Surgical Procedures Pain Pain management Pathogenesis Pathologic Pathway interactions Periosteum Phenotype Phosphoric Monoester Hydrolases Protein phosphatase Proteins Proteomics Publishing RNA Randomized Rattus Reporter Role Saline Sensory Skin Spinal Ganglia Substance P Testing Time Tissues Traumatic Arthropathy Work afferent nerve aggrecan allodynia articular cartilage cartilage degradation cartilage regeneration experimental study healthy volunteer in vivo induced pluripotent stem cell inhibitor innovation joint stiffness multidisciplinary nerve supply neurofilament osteoarthritis pain pain behavior pain reduction pain relief palliative prevent regenerative sham surgery small molecule inhibitor subchondral bone transcriptome transcriptomics

项目摘要

ABSTRACT Osteoarthritis (OA) is a progressive and debilitating disease characterized by deterioration of articular cartilage and pathologic changes to other tissues leading to joint stiffness and pain. Non-surgical treatments focus on behavior modifications and pain relief, but little is known about the molecular pathways controlling nociception during OA pathogenesis. In this project, we will examine how controlling the activity of PHLPP phosphatases contributes to joint innervation in vivo and neurite extension in vitro. We identified PHLPPs as suppressors of chondrocyte regeneration and pain-related behaviors. PHLPP1 and PHLPP2 are present in human and mouse sensory neurons and abnormally expressed in human OA cartilage. In an animal model of OA, intra-articular injection of PHLPP inhibitors prevented joint hypersensitivity and cartilage degradation and reduced sensory neuron innervation of joint tissues (e.g., subchondral bone, periosteum). PHLPP inhibitors suppressed outgrowth of small/medium sensory neurons and expression of neurotransmitters and neurofilaments in vitro. The goal of this project is to determine the mechanisms by which small molecule inhibitors of PHLPP phosphatases suppress OA-associated pain. The central hypothesis is that PHLPP inhibitors prevent innervation of osteoarthritic joints and alter molecular pathways controlling sensory neurite extension. We will study mechanisms by which PHLPP inhibitors prevent neurite extension and joint pain after knee injury with sensitive murine reporters of innervation and with human iPSC- derived sensory neuron model systems.

抽象的骨关节炎（OA）是一种渐进式衰弱的疾病，其特征是关节软骨恶化以及导致关节刚度和疼痛的其他组织的病理变化。非手术治疗的重点行为改变和缓解疼痛，但对控制伤害感受的分子途径知之甚少在OA发病机理中。在这个项目中，我们将研究如何控制PHLPP磷酸酶的活性在体内和神经突延伸的体外有助于关节神经。我们确定PHLPP是软骨细胞再生和与疼痛相关行为的抑制。 phlpp1和 PHLPP2存在于人和小鼠感觉神经元中，并在人OA软骨中异常表达。在OA的动物模型中，关节内注射PHLPP抑制剂可防止关节过敏和软骨降解和关节组织的感觉神经元神经支配（例如，软骨下骨，骨膜）。 pHLPP抑制剂抑制了中小型感觉神经元的生长和表达体外神经递质和神经丝。该项目的目的是确定 PHLPP磷酸酶的小分子抑制剂抑制与OA相关的疼痛。中央假设是PHLPP抑制剂防止骨关节关节支配并改变分子途径控制感觉神经突延伸。我们将研究PHLPP抑制剂预防神经突的机制膝盖损伤后的伸展和关节疼痛，具有敏感的神经支配者和人类IPSC- 派生的感觉神经元模型系统。