This submission outlines a five-year mentored training plan for the career development of a physician-scientist to characterize the regulatory role of the short non-coding RNA, microRNA-146a, in B cell activation and function, and examine this in human systemic lupus erythematosus (SLE) patients. MicroRNA-146a has been characterized as a negative regulator of the NF?B and interferon signaling pathways in myeloid and/or T cells, but its function in B cells is not well defined. Because microRNAs often target different pathways in immune cells, this proposal serves to fill this gap in knowledge in B cells to better understand its dysregulation in human SLE disease. A combination of cellular immunology, molecular biology, and RNA sequencing/bioinformatics analysis will be used to rigorously characterize microRNA-146a's role in activated B cells. In addition, both a hypothesis based and discovery based approach will seek to identify novel gene targets. Furthermore, this proposal will examine microRNA-146a's B cell expression in relationship to human SLE activity and flare, thus probing its translational use as a novel disease biomarker. This project is consistent with NIAMS goals of advancing research in human SLE, which has been challenging in part due to difficulties in assessing ongoing disease activity, which this proposal attempts to address. The applicant is currently in her 4th year as a PhD Candidate via the UCLA STAR physician-scientist program under the mentorship of her current thesis advisor, Dr. Dinesh Rao, an expert in non-coding RNA biology. The proposed 5-year K08 training period will be under the scientific mentorship of Dr. Rao and Dr. Alexander Hoffmann, a long time collaborator, whose expertise is in quantitative experimentation and bioinformatics analysis in inflammatory gene signaling pathways. In addition, the applicant will receive clinical/translational research mentorship from Dr. Maureen McMahon, Director of UCLA's Lupus Clinical Trials Center, who has long-standing experience with SLE clinical trial methodology and biomarker discovery. The new molecular techniques, bioinformatics analysis, and translational skills will be broadly applicable to microRNAs in autoimmune diseases. This training proposal will provide the necessary mentorship and support for the applicant to develop into a successful independent investigator.
MicroRNAs are short non-coding RNAs that are important mediators of gene expression, and have been found to be dysregulated in autoimmune diseases. They show promising use as biomarkers of disease activity, although the lack of defined function in immune responses has hindered clinical translation. By characterizing the regulatory role of microRNA-146a in B cell immunity, we hope to better understand its role in systemic lupus erythematosus pathogenesis and further evaluate its use as a disease activity biomarker.