Elucidating the role of protein translation efficiency in t cell adaptation to human skin - proposal summary/abstract t cell-mediated inflammatory and autoimmune skin diseases affect millions…

The National Institute of Arthritis and Musculoskeletal and Skin Diseases awarded the University of Pennsylvania $2,063,666 on June 1, 2026, under the Arthritis, Musculoskeletal and Skin Diseases Research program (CFDA 93.846) to investigate protein translation efficiency in T cell adaptation to human skin.

The research addresses tissue-resident memory T cells (TRM) that persist in skin despite current immunosuppressive treatments and drive chronic inflammatory and autoimmune skin disease. The study combines genome-wide CRISPR/Cas9 screening, single-cell spatial transcriptomics, epigenetic profiling, intravital imaging, stable isotope labeling, and polysome profiling to determine when and where protein translation efficiency becomes critical for T cells to establish tissue residence. A third aim evaluates therapeutic strategies targeting translation termination to selectively eliminate TRM—comparing systemic small-molecule degraders with targeted lipid nanoparticle delivery of gene editing components—while preserving circulating T cells.

Work is performed in Philadelphia, Pennsylvania, with a period of performance from June 1, 2026, through May 31, 2030. This is a Project Grant, the standard NIH investigator-initiated research mechanism.

Elucidating the role of protein translation efficiency in t cell adaptation to human skin - proposal summary/abstract t cell-mediated inflammatory and autoimmune skin diseases affect millions worldwide, with healthcare costs exceeding $100 billion annually in the united states alone. Current treatments targeting cytokine pathways often fail to achieve lasting remission due to the persistence of tissue-resident memory t cells (TRM) in the skin. The molecular mechanisms enabling human TRM to persist in the challenging skin environment remain unknown, preventing development of more effective therapeutic strategies. Through an unbiased genome-wide crispr/CAS9 knock-out screen in a human skin xenograft model, we discovered that protein translation efficiency is essential for TRM survival. This proposal investigates this newly discovered molecular pathway controlling t cell tissue residence through regulation of protein translation efficiency. In aim 1, we will determine when and where protein translation efficiency in t cells becomes critical to establish tissue residency using single-cell spatial transcriptomics, epigenetic profiling, and intravital imaging. By tracking t cells in real-time within human skin tissue, we will reveal the precise checkpoints where efficient protein translation enables tissue adaptation. In aim 2, we will define how protein translation efficiency controls the TRM- specific protein synthesis program through stable isotope labeling and polysome profiling. This will uncover how TRM adapt their protein synthesis machinery to survive in the nutrient-limited skin environment. In aim 3, we will evaluate therapeutic strategies targeting translation termination to selectively eliminate TRM, comparing systemic small molecule degraders with targeted lipid nanoparticle delivery of gene editing components. These complementary approaches will determine the most effective method for therapeutic targeting of TRM while sparing beneficial circulating t cells. Our innovative approach combines: 1) the first genome-wide functional screen in human TRM, 2) cutting-edge spatial and molecular technologies to study translation control in human tissue, and 3) immediate therapeutic applications through clinical-stage compounds. Conceptually, this work departs from the status QUO and has the potential to transform our understanding of human TRM biology by revealing how protein translation efficiency enables tissue adaptation while providing mechanistic justification for therapeutic targeting of translation termination in t cell-mediated skin diseases. Success could lead to paradigm-shifting treatments that selectively eliminate TRM, offering lasting remission for millions affected by chronic inflammatory skin conditions that are mediated by t cells.