Methylglyoxal-mediated activation of the integrated stress response promotes eIF2A-dependent translation in diabetic neuropathic pain

About This Grant

Project Summary/Abstract Diabetic neuropathic pain (DNP) is a debilitating complication of diabetes that affects millions of individuals worldwide, yet its underlying molecular mechanisms remain poorly understood, and effective treatments are limited. Emerging evidence implicates methylglyoxal (MGO), a reactive glycolysis byproduct, in the development of DNP, potentially through activation of the integrated stress response (ISR). The ISR regulates mRNA translation under cellular stress and has been linked to nociceptor hyperexcitability. Our research seeks to investigate how MGO-induced ISR activation alters translational control in nociceptors, with a specific focus on the role of eIF2A in driving ISR-mediated protein synthesis that contributes to pain hypersensitivity in DNP. Specific Aim 1 will use a translational approach that integrates next-generation sequencing (TRAP-seq, Ribo- seq) in mouse and humans. Specific Aim 2 will utilize gene editing (CRISPR-Cas9), and functional assays (calcium imaging, pain behavior) in mouse, rat, and human nociceptors. Together, the aims will define conserved and species-specific mechanisms linking diabetes, ISR activation, and nociceptor dysfunction. This fellowship will provide rigorous training in molecular neuroscience, RNA sequencing, bioinformatics, and translational diabetes and pain research to ensure a strong foundation in both experimental and computational techniques. The training environment consists of collaborative research setting with access to state-of-the-art sequencing technologies, primary human DRG cultures, and established preclinical models of diabetes, offering an unparalleled opportunity to bridge mechanistic studies with clinical relevance. By investigating novel ISR-driven mechanisms underlying nociceptor dysfunction in DNP, this project aims to identify new molecular targets for objective DNP diagnosis, developing new models to study DNP, for possible new avenues for therapeutic intervention, and improving the quality of life for individuals with diabetes.