Harnessing cutaneous transcriptional and myeloid cell signatures to understand treatment response in juvenile dermatomyositis

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Juvenile dermatomyositis (JDM) is a potentially life-threatening pediatric autoimmune disease that frequently first presents with cutaneous inflammation and can progress to debilitating muscle weakness, calcinosis, and severe lung disease. Two-thirds of children do not respond to initial treatment, and there is a lack of prognostic biomarkers and targeted treatments. Thus, there is a critical need to develop a better understanding of cellular disease mechanisms and molecular heterogeneity to advance precision medicine. Deeper investigation of molecular disease signatures at the tissue level, where active inflammation frequently persists, holds the potential to delineate novel disease mechanisms, biomarkers and treatment targets. The specific scientific aims of this project are to 1) Utilize cutaneous and peripheral blood gene expression signatures to determine biology and predictors of JDM treatment response and 2) Determine single-cell and spatial transcriptional phenotypes of myeloid cells within skin and blood that are associated with treatment refractory JDM. Through a longitudinal approach and non-invasive skin sampling methodology in a well-phenotyped JDM cohort, the candidate will characterize cutaneous transcriptomic signatures in both lesional and non-lesional skin as related to treatment response. The candidate will leverage paired blood samples to directly compare the importance of tissue-specific signatures in biomarker development. Cutaneous myeloid cell populations in treatment refractory JDM patients will additionally be assessed at a single-cell level with spatial resolution to better understand the potential role of myeloid cells as mediators of cutaneous inflammation and dermal-systemic immune crosstalk. The applicant is an Assistant Professor and Pediatric Rheumatologist at the University of Michigan and actively treats children with JDM. Her long-term career goal is to advance knowledge of disease mechanisms, identify novel biomarkers and discover therapeutic targets in JDM in order to improve care for her patients. To become an independent physician scientist with expertise in molecular and cellular mechanisms of pediatric autoimmune disease, the candidate will accomplish the following scientific training goals: 1) gain expertise in working with additional patient biosamples and primary cells, specifically using keratinocytes and myeloid cells, as a model to study immune dysregulation in JDM, 2) develop skills in the application of bioinformatic, single-cell and systems biology approaches to the study of pediatric autoimmune disease, and 3) gain expertise in study design, integration and analysis of molecular and clinical patient-oriented data. The candidate will also complete the following career development goals: 1) develop skills to lead a translational research team and mentor trainees, 2) improve written and oral communication skills and 3) establish a multicenter research network. The applicant has formed an engaged team of mentors and advisors with expertise in keratinocyte biology, immunology, bioinformatics, single-cell methods and systems biology approaches to integration of patient-oriented data to guide her in the proposed study and career development goals.