Harnessing single cell RNA sequencing and integrative bioinformatics to identify precision therapeutics for dermatomyositis

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Project Abstract Dermatomyositis (DM) is a complex immune-mediated systemic condition affecting children and adults for which there are few approved treatments. The mainstay of treatment includes high-dose corticosteroids, which are associated with long-term steroid-related damage. While mortality has improved since the introduction of corticosteroids, over 60% of children and 80% of adults with DM, still experience long-term functional impairment, highlighting the need for improved therapies. Refractory skin disease is especially difficult to treat with only ~1/3 of patients attaining clinical remission. However, DM-specific therapeutic development has been hindered because of the rarity of the disease, few preclinical animal models, and the time and cost associated with traditional drug development pipelines. To circumvent these barriers and identify precision medicine treatments for DM, we propose a novel computational drug repositioning strategy to identify existing compounds that target perturbed molecular networks in DM-associated cell types using a combination of single-cell network analyses, transcriptomic-based computational drug repurposing, and ex-vivo cell culture assays in PBMCs and skin. In Specific Aim 1, we will identify the cell-specific immune pathways dysregulated in juvenile DM PBMCs and DM skin compared to healthy controls using single-cell RNA sequencing. In Specific Aim 2, we will apply transcriptomic-based computational drug repurposing to identify single agent and combination therapies that target cell-specific immune signatures in peripheral blood and skin. In Specific Aim 3, we will determine the effects of predicted single agent and combination therapies on immune cell activation using ex-vivo PBMC and skin culture assays. We expect the summary of this work to advance knowledge of DM pathogenesis at the cellular level and to rapidly identify compounds that can be repurposed for the treatment of DM with the long-term goal of improving disease outcomes. The candidate’s career goal is to become a translational researcher and computational immunologist investigating the immune dysregulation of rheumatic diseases to inform precision medicine approaches to care. In this K08 proposal, the candidate has developed a career development plan, which requests training in advanced single cell analysis methods, computational drug repurposing, and translational immunology to gain the skills needed to achieve this goal. The candidate is trained in Pediatric Rheumatology and holds a faculty position at the University of California, San Francisco. The candidate has assembled a mentorship and advisory team with expertise in integrative bioinformatics, basic immunology, skin immunology, systems biology, translational research, and clinical trials. The scientific environment at this institution, superb mentorship and advisory team supporting the candidate, and proposed research aims will enable the candidate’s transition to an independent career as a physician scientist dedicated to developing precision medicine approaches to care for people with rare rheumatic conditions.