Project Summary/Abstract
Idiopathic inflammatory myopathies (IIM) are systemic autoimmune diseases characterized by specific
autoantibodies and upregulation of interferon inducible genes but are not completely understood. We propose
a testable novel hypothesis in this K08 award to study the role of short interspersed elements (SINEs) in IIM.
SINEs occupy approximately 13% of the genome, are capable of forming double stranded RNA that leads to
activation of the innate immune system and production of interferons through MDA5 signaling. This is normally
prevented by ADAR1 which edits adenosine to inosine in RNA, thereby disrupting the double strandedness of
the structure. The long-term goal of this proposal is to achieve a better understanding of the underlying
molecular mechanisms of disease in IIM that may lead to better therapeutics with improved efficacy and lower
risk of adverse effects. This may additionally shed light on certain aspects of autoimmunity in general and the
specificity of autoantibodies. Aim 1 uses muscle data to study the transcriptome for evidence of SINE
overexpression and to quantify RNA editing in IIM and healthy controls. Aim 2 utilizes single cell analysis of the
transcriptome and epigenome to identify cell types that contribute the most to interferon production in
inflammatory myositis. Aim 3 correlates mutation detection and alternative splicing of ADAR1 and MDA5 with
interferon inducible genes. We expect this research plan to unveil novel biology in IIM. The candidate is an
MD/MPH rheumatologist at the University of Washington, with a background in immunology, statistics, and
computer programming, the proposed research and mentoring plans will ensure rigorous training in advanced
immunology, bioinformatics methodologies, and scientific communication to become a successful independent
scientist. Dr. Najjar is committed to a career in scientific research using bioinformatics tools to study complex
autoimmune disorders. The primary mentor is Dr Tomas Mustelin, MD, PhD who has mentored many scientists
throughout his career. The mentoring team will include additionally Dr Arnon Arazi, PhD as a co-mentor and Dr
Robert Bradley, PhD as a scientific advisor, both are experts in computational biology. The University of
Washington is an excellent environment for scientific research with advanced infrastructure for genomic
research. We will utilize the available genomic centers including that of Dr Michael Gale, PhD to study the
transcriptome and epigenome at the single cell level. The proposed multidisciplinary training program will
ensure Dr. Najjar's transition to an independent investigator.
