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:
- 金额:$ 20.99万
- 依托单位:
- 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:
- 关键词:Afferent NeuronsAnimal ModelArthralgiaBehaviorBehavior TherapyBiological AssayBiological ModelsCartilageCellsChondrocytesChronicConfocal MicroscopyDataDegenerative polyarthritisDeteriorationDevelopmentDiseaseFibroblastsGoalsHumanHypersensitivityImmobilizationImmunohistochemistryIn VitroInduced pluripotent stem cell derived neuronsInjectionsInjuryIntra-Articular InjectionsJointsKnee InjuriesKnowledgeLaboratoriesMeasuresMedial meniscus structureMitochondriaMolecularMouse StrainsMusNatural regenerationNerve FibersNeuritesNeuronsNeurotransmittersNociceptionOperative Surgical ProceduresPainPain managementPathogenesisPathologicPathway interactionsPeriosteumPhenotypePhosphoric Monoester HydrolasesProtein phosphataseProteinsProteomicsPublishingRNARandomizedRattusReporterRoleSalineSensorySkinSpinal GangliaSubstance PTestingTimeTissuesTraumatic ArthropathyWorkafferent nerveaggrecanallodyniaarticular cartilagecartilage degradationcartilage regenerationexperimental studyhealthy volunteerin vivoinduced pluripotent stem cellinhibitorinnovationjoint stiffnessmultidisciplinarynerve supplyneurofilamentosteoarthritis painpain behaviorpain reductionpain reliefpalliativepreventregenerativesham surgerysmall molecule inhibitorsubchondral bonetranscriptometranscriptomics
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Nathan P Staff其他文献
Nathan P Staff的其他文献
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{{ truncateString('Nathan P Staff', 18)}}的其他基金
The Mayo Clinic NeuroNEXT Clinical Research Site
梅奥诊所 NeuroNEXT 临床研究网站
- 批准号:
10743328 - 财政年份:2023
- 资助金额:
$ 20.99万 - 项目类别:
Investigating the role of MAP2 in chemotherapy-induced peripheral neurotoxicity
研究 MAP2 在化疗引起的周围神经毒性中的作用
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10559108 - 财政年份:2023
- 资助金额:
$ 20.99万 - 项目类别:
Assessment of Chemotherapy-Induced Peripheral Neuropathy Susceptibility Using Patient-derived iPSC Technology
使用患者来源的 iPSC 技术评估化疗引起的周围神经病变的易感性
- 批准号:
9763518 - 财政年份:2017
- 资助金额:
$ 20.99万 - 项目类别:
Assessment of Chemotherapy-Induced Peripheral Neuropathy Susceptibility Using Patient-derived iPSC Technology
使用患者来源的 iPSC 技术评估化疗引起的周围神经病变的易感性
- 批准号:
9450944 - 财政年份:2017
- 资助金额:
$ 20.99万 - 项目类别:
Mechanisms of Bortezomib-induced Peripheral Neuropathy
硼替佐米诱发周围神经病变的机制
- 批准号:
9093719 - 财政年份:2012
- 资助金额:
$ 20.99万 - 项目类别:
Mechanisms of Bortezomib-induced Peripheral Neuropathy
硼替佐米诱发周围神经病变的机制
- 批准号:
8677584 - 财政年份:2012
- 资助金额:
$ 20.99万 - 项目类别:
Mechanisms of Bortezomib-induced Peripheral Neuropathy
硼替佐米诱发周围神经病变的机制
- 批准号:
8505004 - 财政年份:2012
- 资助金额:
$ 20.99万 - 项目类别:
Mechanisms of Bortezomib-induced Peripheral Neuropathy
硼替佐米诱发周围神经病变的机制
- 批准号:
8350911 - 财政年份:2012
- 资助金额:
$ 20.99万 - 项目类别:
Dopaminergic modulation of CA1 intrinsic excitability
CA1 内在兴奋性的多巴胺能调节
- 批准号:
6719028 - 财政年份:2002
- 资助金额:
$ 20.99万 - 项目类别:
Dopaminergic modulation of CA1 intrinsic excitability
CA1 内在兴奋性的多巴胺能调节
- 批准号:
6634372 - 财政年份:2002
- 资助金额:
$ 20.99万 - 项目类别:
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