Federal Grant Award Summary

The National Institute of Neurological Disorders and Stroke (NINDS) awarded $650,057 to the University of Pittsburgh under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) for a five-year project spanning September 1, 2026, through August 31, 2031. This R01 Project Grant supports research investigating the molecular mechanisms by which Matrin-3 (MATR3) mutations drive neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The research deliverables include the development and characterization of robust disease models in Drosophila and mice, identification of genetic and protein interactors that modify MATR3 toxicity, and comprehensive mechanistic analysis of MATR3 aggregation and RNA-binding protein dysfunction through integrated genetic screening, transcriptomic analysis, and validation in human patient tissues.

The project specifically focuses on three research objectives: defining how the heterogeneous nuclear ribonucleoprotein M (HNRNPM) modulates MATR3-driven neurotoxicity using knock-in mouse models; identifying conserved genetic modifiers through parallel screens in Drosophila, induced pluripotent stem cell (iPSC)-derived neurons, and transgenic mice; and uncovering mechanisms of MATR3 aggregation using optogenetics and postmortem tissue analysis. These research outputs are designed to advance understanding of ALS/FTD pathophysiology and may inform development of targeted therapeutic interventions for these severe neurodegenerative disorders.