Integrative genomic analysis of the human response to glucocorticoids

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

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Abstract

Below is a summary of the key scientific contributions made by our laboratory over the past year: 1. Neutrophils are a key target of glucocorticoids: During the past four years, we have studied the response of human and rhesus macaque neutrophils to glucocorticoids. Through an in vivo study in which we administered the glucocorticoid methylprednisolone to a group of 20 healthy volunteers, then sampled individual immune cells serially from peripheral blood, we were able to study the transcriptional response to glucocorticoids in highly pure neutrophils. Surprisingly, neutrophils appear to be the most transcriptionally responsive cell type to glucocorticoid administration. A series of follow-up in vitro and in vivo studies have revealed the molecular basis for this strong transcriptional response and have revealed specific signaling pathways that are important for neutrophil function and repressed functionally by glucocorticoids. 2. Deciphering migration and localization patterns of neutrophils: Through a research collaboration involving six laboratories across four NIH institutes and one extramural collaborator, we have performed live-tracking of rhesus macaque and cynomolgus macaque neutrophils by PET-CT imaging, in vivo flow cytometry, and RNA sequencing, in homeostasis and upon glucocorticoid administration. These experiments are allowing us to study the effects of glucocorticoids on neutrophil migration, and to contribute to long-standing questions regarding neutrophil kinetics and localization. 3. Development of a platform for cell-targeted delivery of glucocorticoids: In collaboration with NCATS, we have developed a platform for targeted delivery of glucocorticoids to human primary immune cells. 4. Challenging the existing model of glucocorticoid receptor localization and regulation: Through our work in human primary cells and tissues, we have found that the longstanding model of glucocorticoid receptor localization and regulation applies to cancer cell lines but not to primary cells.