Federal Grant Award Summary

The University of Michigan received a $443,000 Project Grant from the National Institute of Neurological Disorders and Stroke (NINDS) under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853), awarded June 1, 2026, with a completion date of May 31, 2028. This research project delivers a comprehensive scientific investigation into the dominant-negative effects of neuropathy-associated transfer RNA synthetase (tRNA synthetase) variants through an innovative pipeline incorporating genetic, molecular, in vitro, and in vivo approaches. The primary research outputs will include mechanistic characterization of how aminoacyl-tRNA synthetase (ARS) mutations cause dominant axonal neuropathy, with initial focus on the well-characterized R329H alanyl-tRNA synthetase (AARS1) variant and planned expansion to all seven ARS loci associated with dominant neuropathy.

The grant-funded research will produce validated scientific methodologies and findings that address two critical questions: whether neuropathy-associated ARS variants operate through dominant-negative mechanisms, and the specific mechanisms and degree to which these variants impact tRNA charging and cellular stress pathways. Deliverables include experimental data from enzyme kinetic assays, genetic complementation studies, and model organism systems (yeast and C. elegans), culminating in an innovative, scalable strategy for studying neuropathy-associated variants across multiple ARS loci. These research outputs will advance fundamental understanding of neurological disease pathophysiology and potentially inform therapeutic development strategies for dominant neuropathies associated with ARS mutations.