Project Grant R15AG104244

The National Institute on Aging awarded East Carolina University $512,882 under the Aging Research program (CFDA 93.866) on September 1, 2026, to conduct optogenetic dissection of EPHA1 missense mutations implicated in Alzheimer's disease.

The research employs an optogenetic strategy to precisely control EPHA1 receptor tyrosine kinase activation in live cells, enabling rigorous investigation of how Alzheimer's-associated mutations (R791H, H888Y, and R926C) affect neuronal signaling and function. In the first aim, the team will engineer optogenetic EPHA1 constructs carrying each mutation and validate their biochemical activity and downstream signaling in HEK293 cells. The second aim expresses these constructs in mouse dissociated neuron cultures and human iPSC-derived neurons to examine how mutant EPHA1 alters canonical signaling pathways (MAPK/ERK, PI3K/AKT, and GSK3B) and to measure effects on neuronal morphology, synaptic density, and cell viability. The third aim uses multi-electrode array recordings to determine how mutant EPHA1 impacts network activity and synaptic function, and tests whether GSK3B inhibitors can reverse functional deficits caused by hyperactive signaling.

Performance occurs in Greenville, North Carolina, with project period from September 1, 2026, through August 31, 2029. This is a Project Grant, classified as assistance funding to a research institution.