Investigating single-T cell atopic gene networks in Asian and Hispanic genetic backgrounds - Investigating single-T cell atopic gene networks in Asian and Hispanic genetic backgrounds Project Summary/Narrative Immunomodulatory therapies now robustly improve atopic dermatitis, based on selective targeting of cytokine pathways. However, no immune cell-specific molecular biomarkers can currently differentiate disease states at the level of individual patients or genetic ancestries, to help guide treatment selection. Our long-term objective is to understand causes and effective treatments for atopic dermatitis in Asian and Hispanic genetic backgrounds. The objective of this proposal is to identify genetic biases in, and functionally characterize, a set of abnormally elevated transcripts in atopic dermatitis skin T cells, which we recently discovered in a cohort of Asian and Hispanic patients. Our central hypothesis is that transcriptional abnormalities in skin-resident T cells are upstream, causative drivers in atopic dermatitis and once validated, represent candidate biomarkers for drug response. The rationale underlying this proposal is that prior work suggests that non-European cohorts develop atopic dermatitis via genetic pathways outside canonical Th2/Tc2 signaling, a model not supported by our preliminary data. We will validate our abnormal atopic T cell signature in Asian and Hispanic cohorts and experimentally test our hypothesis that specific genes in this signature can produce a Th2 cell identity. We will pursue these aims using innovative technical approaches that include both CRISPR/Cas9-based gene activation in primary T cells and single-cell spatial transcriptomics, bringing new capabilities to the skin immunology field. Our proposal is significant because it investigates patient-level biomarkers in atopic dermatitis T cells in diverse genetic backgrounds. The expected outcome of this proposal is a population- and mechanism-validated set of genetic abnormalities that typify atopic dermatitis in Asian and Hispanic patients. These data will have a positive impact on clinical treatments because they will guide treatments to reduce the substantial morbidity and economic impact stemming from atopic dermatitis in non-European patients.
