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.
