Using Bioinformatics Methodologies to Explore the Role of Short Interspersed Elements in the Pathogenesis of Idiopathic Inflammatory Myopathies

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.