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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.

摘要骨关节炎（OA）是一种以关节软骨退化为特征的进行性和使人衰弱的疾病以及导致关节僵硬和疼痛的其他组织的病理变化。非手术治疗的重点是行为改变和疼痛缓解，但对控制伤害感受的分子途径知之甚少在OA发病过程中。在这个项目中，我们将研究如何控制PHLPP磷酸酶的活性，有助于体内的关节神经支配和体外的神经突延伸。我们确定PHLPPs作为软骨细胞再生和疼痛相关行为的抑制因子。PHLPP 1和 PHLPP 2存在于人和小鼠感觉神经元中，并且在人OA软骨中异常表达。在OA动物模型中，关节内注射PHLPP抑制剂可预防关节过敏，关节组织的软骨退化和减少的感觉神经元神经支配（例如，软骨下骨，骨膜）。PHLPP抑制剂抑制小/中型感觉神经元的生长和神经递质和神经丝。本项目的目标是通过以下方式确定机制：所述PHLPP磷酸酶的小分子抑制剂抑制OA相关疼痛。中央假设是PHLPP抑制剂阻止骨关节炎关节的神经支配并改变分子途径控制感觉神经突的延伸我们将研究PHLPP抑制剂阻止神经突生长的机制，膝关节损伤后的伸展和关节疼痛与神经支配的敏感鼠报告基因和人iPSC- 衍生的感觉神经元模型系统。