Elucidating the Role of Phosphorylated Sox9 in Regulating Glycolytic Activities in Neuropathic Pain Pathogenesis

Project: Research

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Description

Neuropathic pain (NP) is caused by injury or diseases of the nervous system affecting around 7-10% of population worldwide. Current treatments for NP are either ineffective with pain relapse or are associated with undesirable side effects, highlighting the need for novel therapies. Many studies have revealed that metabolic reprogramming controls astrocytes activities and functional consequences, contributing to the pathogenesis of neurological disorders. To date, drug- or energy-based therapies that target metabolic abnormality have greatly improved their treatments. Reactive astrogliosis with impaired metabolites productions in dorsal horn is also one of key mechanisms in driving NP. Nevertheless, similar targeting strategies are less explored as the characteristics and molecular regulation of metabolic alterations that underlie NP development remain unclear. Addressing above issues will help in understanding the complex pathophysiology of NP and provide alternative therapeutic strategies to improve the current treatments.Using RNA-sequencing and metabolomics, we found that enhanced glycolysis in astrocytes is highly associated with induction of astrocytes reactivity and pain responses following the spared nerve injury (SNI). Inhibition of glycolysis attenuated mechanical allodynia. To explore the upstream effector in regulating the process, we identified Sox9, a key transcriptional factor for astrocytogenesis, which also plays critical roles in metabolic reprogramming. SNI promoted phosphorylation of Sox9, which was positively correlated with the glycolytic activation in astrocytes and NP development. Loss- and gain-of-function studies showed that phosphorylated Sox9(p-Sox9) is required for the upregulation of glycolytic genes and pain responses. Notably, two glycolytic genes, HK2 and LDHA, showed the most dramatic changes in expression levels upon genetic manipulation of p-Sox9. Importantly, the promoter regions of HK2 and LDHA contain putative Sox9 binding motifs, suggesting a direct transcriptional regulation. Based on these data, we hypothesized that p-Sox9 promotes transcriptional activation of glycolytic genes, HK2 or/and LDHA, that boosts up the glycolytic activity in astrocytes. The altered metabolic state drives deleterious reactive astrogliosis that possibly also associated with the activation of other glial/neuronal pain signaling, contributing to NP development. In this proposal, we will: 1) explore the pathological role of enhanced glycolysis in NP, 2) determine the role of phosphorylated Sox9 in NP pathogenesis, and 3) investigate the molecular mechanisms underlying phosphorylated Sox9-mediated glycolytic activity in pain pathogenesis. Our proposed studies will unravel new mechanistic insights into how posttranslational modification of a transcriptional factor contributes to metabolic shifts in pain pathogenesis, laying the foundation for developing energy/metabolic-based therapy for pain management.

Detail(s)

Project number9043470
Grant typeGRF
StatusNot started
Effective start/end date1/01/23 → …