Understanding transcriptional connections between cutaneous and systemic lupus

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 DESCRIPTION (provided by applicant): Systemic Lupus Erythematosus (SLE) is a devastating autoimmune disease that affects up to 0.5% of the US population. This disease is characterized by heterogeneous manifestations including severe rashes, organ- threatening nephritis, and an elevated risk of cardiovascular disease. Despite ongoing research into the pathogenesis of this disease, very little is understood about the mechanism of cutaneous lesion development or how skin inflammation may be able to influence systemic disease. This project proposes to take a systems biology approach to analyze the gene expression changes present in the most common cutaneous lupus subtypes by taking advantage of advances in RNA isolation from formalin-fixed paraffin-embedded tissue. Importantly, changes in gene expression and regulation of inflammatory networks will then be analyzed to determine pathways unique to cutaneous lupus associated with systemic disease. Further, comparisons with known dysregulated pathways in lupus nephritis biopsies will be made to develop an understanding of the overlap in the pathology between cutaneous and renal lupus. Importantly, cutaneous transcriptional changes will be analyzed in the context of available clinical data to determine if cutaneous biomarkers may exist that predict development of systemic lupus. Study Design: Using microarray analysis of subacute cutaneous (sCLE) and discoid lupus (DLE) skin biopsies, AIM 1 will develop a comprehensive understanding of the gene expression changes in sCLE and DLE compared with control skin. Using Ingenuity and Genomatix software, changes to biological pathways and transcriptional networks will be identified. Further, overlapping and unique transcriptional changes between the disease subsets will also be determined. The information gathered in AIM1 and additional biopsy subsets will then be used to compare cutaneous changes in gene expression in skin only CLE to CLE associated with systemic disease (Aim2a). Further, the pathways and networks unique to DLE, sCLE, skin- only CLE and CLE with systemic disease will be compared to those known to be dysregulated in kidney biopsies from lupus nephritis patients via TALE (Tool for Approximate LargE graph matching) analysis (AIM2b). This will allow for identification of overlapping expression changes and inflammatory networks between cutaneous and renal inflammation which may be important targets for further study and treatments. AIM2c will use Chi-squared and survival analysis to determine the extent to which gene expression changes and dysregulated networks identified in AIM 1 correlate with the development of systemic disease manifestations, either at the time of biopsy or over time. This would then allow for development of possible biomarkers of systemic disease risk and identify important targets for disease prevention and treatment strategies.