Project Grant R03NS149107

The National Institute of Neurological Disorders and Stroke (NINDS) awarded The Washington University a Project Grant of $155,500 under the Extramural Research Programs in the Neurosciences and Neurological Disorders (CFDA 93.853) program, with an award date of June 1, 2026 and completion date of May 31, 2028. The research project, titled "Mapping Mitochondrial NADPH Utilization by Exploiting Hypomorphic Variants of NADK2," will generate a series of cell lines harboring NADK2 (NAD+ kinase 2) variants to elucidate the functional allocation of mitochondrial NADPH (nicotinamide adenine dinucleotide phosphate) across metabolic pathways.

The research deliverables will advance understanding of how reduced NADK2 activity selectively affects specific metabolic processes while sparing others, thereby establishing a "priority code" for mitochondrial cofactor utilization. This mechanistic framework will illuminate disease heterogeneity in patients with NADK2 mutations and progressive encephalopathy with leukodystrophy due to DECR deficiency. The findings are expected to contribute to understanding how partial loss of NADPH production differentially impacts metabolic pathways including unsaturated fatty acid oxidation, lysine catabolism, type II fatty acid synthesis, and proline biogenesis, ultimately informing therapeutic approaches for this ultra-rare neurological disorder.