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Elucidating the role of protein translation efficiency in T cell adaptation to human skin

Award Number: R01AR086989
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $2,063,666 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	5/19/2026	NEW	$2,063,666
														Subtotal = $2,063,666

Grand Total All Awards = $2,063,666

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Elucidating the role of protein translation efficiency in T cell adaptation to human skin

Award Number: R01AR086989

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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