Project Grant R21AG099004

Federal Grant Award Summary

The University of Pennsylvania received a $425,235 Project Grant from the National Institute on Aging under the Aging Research program (CFDA 93.866) for the period February 1, 2026 through January 31, 2028. This award supports research to decode antigen-specific T cells in frontotemporal degeneration (FTD), a neurodegenerative disorder characterized by progressive frontal and/or temporal lobe atrophy. The research will investigate the role of CD8+ T cells that recognize cryptic peptides derived from aberrant TDP-43 (TAR DNA-binding protein 43) pathology, which occurs in approximately 50% of FTD cases.

The project will establish a causal link between CD8+ T cell activity and FTD disease progression by characterizing antigen targets, functional phenotypes, and temporal dynamics of cryptic peptide-specific T cells in symptomatic and pre-symptomatic C9ORF72-related FTD patients. Conducted in collaboration with the Penn FTD Center, this research will provide foundational insights into the immunological mechanisms underlying FTD pathology and create a framework for developing potential immunotherapeutic strategies targeting cryptic epitope-specific T cells. The work builds upon preliminary data demonstrating that CD8+ T cells recognize validated cryptic peptides and induce cytotoxicity toward TDP-43-affected neuronal cells, positioning the research to advance understanding of T cell-mediated neurodegeneration across related conditions including amyotrophic lateral sclerosis (ALS) and inclusion body myositis (IBM).