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

Award Number: F32DK146743
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/30/2026
PERIOD OF PERFORMANCE END DATE: 09/29/2027

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $76,300 )
2026	2026	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/7/2026	NEW	$76,300
														Subtotal = $76,300

Grand Total All Awards = $76,300

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

Award Number: F32DK146743

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/30/2026

PERIOD OF PERFORMANCE END DATE: 09/29/2027

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