The Role of Sodium Channel Nav1.7 in Osteoarthritis - Resubmission - 1

钠通道 Nav1.7 在骨关节炎中的作用 - 重新提交 - 1

• 批准号: 10390155
• 负责人: Chuanju Liu
• 金额: $ 69.54万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10390155
• 关键词: Ablation; Afferent Neurons; Anabolism; Analgesics; Arthritis; Binding; Biological Assay; Carbamazepine; Cartilage; Catabolism; Chemicals; Chondrocytes; Clinical; Complex; Conditioned Culture Media; Data; Degenerative polyarthritis; Dependence; Development; Disease; Electrophysiology (science); Gene Expression Profiling; Genes; Genetic Polymorphism; Heat-Shock Proteins 70; Human; Inflammation; Inherited; Interleukin-1 beta; Intra-Articular Injections; Lead; Mediating; Mediator of activation protein; Membrane Potentials; Membrane Transport Proteins; Metabolic; Metabolism; Methods; Modeling; Molecular; Mus; Neurons; Nucleotides; Operative Surgical Procedures; Oral; Pain; Pain Disorder; Pathogenesis; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Play; Property; Proteomics; Regulation; Reporting; Research; Role; Series; Small Interfering RNA; Sodium Channel; Spinal Ganglia; Testing; Therapeutic Effect; Transmembrane Transport; arthropathies; differential expression; inhibitor; innovation; insight; joint destruction; knock-down; midkine; new therapeutic target; novel; osteoarthritis pain; overexpression; pain relief; pain sensitivity; prevent; therapeutic target; transcriptome sequencing

Osteoarthritis (OA) is the most common joint disease and currently there is no effective means of preventing or slowing joint degeneration. Thus, identification of new OA-associated molecule(s) may provide invaluable in- formation toward the search for novel therapeutic targets for OA. Our RNAseq screen for novel, differentially expressed genes in OA led to the isolation of Nav1.7 (encoded by SCN9A) as a novel OA-associated molecule. Nav1.7 is of particular significance due to its correlation with a spectrum of hereditary human pain disorders. A nucleotide polymorphism of SCN9A was reported to be correlated with increased pain sensitivity in OA patients. Our preliminary data demonstrated that Nav1.7 was increased in superficial zone chondrocytes in both human OA cartilage and cartilage from a mouse OA model. We were excited to find that blocking Nav1.7 dramatically reduced membrane potential in human chondrocytes. To our knowledge, this is the first evidence demonstrat- ing that sodium channel has electrophysiological function in non-excitable chondrocytes. Hyperpolarization caused by Nav1.7 blockade in chondrocytes results in the alternations of secretome/cross-membrane transport of the proteins. Indeed, both direct blockade of Nav1.7 and incubation with the conditioned medium collected from Nav1.7 inhibitor-treated chondrocytes enhanced chondrocyte anabolism and inhibited IL-1β induced ca- tabolism. Further, a series of proteomics screens isolated HSP70 and midkine from the Nav1.7 blocker-treated conditioned medium as two potential key mediators of Nav1.7 in chondrocytes. More significantly, local and oral delivery of Nav1.7-specific inhibitor protected against OA and reduced OA-associated pain in both surgical- ly- and chemically-induced OA models. The hypothesis of the application is that Nav1.7 plays a pivotal role in chondrocyte metabolism and OA through regulating membrane potential and secretome profiling of chondro- cytes. The Specific Aims are: (1) To elucidate the molecular and cellular mechanisms by which Nav1.7 regu- lates chondrocyte metabolism. We will determine SA#1A) the effects of Nav1.7 blockade, overexpression and deletion on chondrocyte metabolism; SA#1B) the target genes of Nav1.7 that mediate the functions of Nav1.7 in chondrocytes; SA#1C) the molecular determinants in Nav1.7 blocker-treated conditioned medium which medi- ate Nav1.7 regulation of chondrocytes; and SA#1D) the co-factor(s) of Nav1.7 that are involved in Nav1.7 regu- lations of chondrocytes. (2) To define the importance of Nav1.7 in the initiation and progression of OA, and the underlying mechanisms involved. We will determine SA#2A) the effects of global ablation of Nav1.7 on OA ini- tiation and progression; SA#2B) the importance of chondrocyte-expressed Nav1.7 to OA; SA#2C) the depend- ence on HSP70 and midkine of Nav1.7 blockade mediated protection against OA; and SA#2D) the therapeutic effects of pharmacological Nav1.7 blockade on OA and OA-associated pain. Proposed studies will not only ad- vance the field by elucidating Nav1.7 regulation of chondrocytes and OA, but may also lead to the development of Nav1.7 inhibitors as novel diseases-modifying drugs for treating OA rather than just pain relievers.

骨关节炎（OA）是最常见的关节疾病，目前尚无有效的预防手段