Dissertation committee:
Δημήτριος Μπούμπας, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Γεώργιος Μπερτσιάς, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, Πανεπιστήμιο Κρήτης
Παναγιώτης Βεργίνης, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, Πανεπιστήμιο Κρήτης
Δημήτριος Βασιλόπουλος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Μαρία Ρουμπελάκη, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Αντώνιος Φανουριάκης, Επίκουρος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Θέμις Αλισσάφη, Επίκουρη Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Summary:
Systemic Lupus Erythematosus (SLE) is a heterogeneous disease with multi-systemic symptoms and unpredictable disease course. A significant manifestation of SLE is the presentation of renal symptoms, known as Lupus Nephritis (LN), which increases mortality and morbidity. Current management of SLE relies on laboratory biomarkers (i.e. complement levels, anti-dsDNA antibody levels) and physician assessments, while diagnosis and management of LN relies on same biomarkers and requires an invasive kidney biopsy to be confirmed and assessed properly. With the advancement of high-throughput omics technologies, SLE and LN have been characterized at a molecular level and multiple implicated pathways, such as the interferon pathway, have been identified, further adding to the complexity of the disease. Yet, despite the bloom of available literature, information on the involved pathways and their molecular interactions in LN is scarce, impeding the efforts of physicians and researchers. Herein, we highlight the lack of a transcriptomics application as biomarkers in clinical use for LN, the need for an approach closer to the standards of precision medicine in SLE and the necessity of a public reliable resource of molecular interactions in LN. Seeking to tackle these issues, we use RNA-sequencing data from LN patients and focus on the relationship of long non-coding RNAs (lncRNAs) with disease activity. Through a network- based approach, we detect 4 lncRNAs, NRIR and KLHDC7B-DT, which are related to IFN signaling and MIR600HG and FAM30A, which are related to B-cell receptor signaling, and we propose them as promising biomarkers to be used in the clinic. We also examine cis- and trans-targets of these lncRNAs, identifying Interferon Lambda Receptor 1 (IFNLR1) as an important target of MIR600HG and FAM30A, thus suggesting a possible way through which these lncRNAs regulate B-cells. Furthermore, we use transcriptomics data from SLE patients combined with an unbiased clustering approach to identify molecular endotypes in SLE. We identify 5 endotypes which recapitulate the spectrum of pathophysiological processes previously identified in lupus and continue our analysis utilizing the iLINCS tool to propose compounds with potential to restore the deregulated transcriptome of the SLE endotypes. Given the fact the monocytes, an innate immune cell type, is a central component involved in the pathogenesis of SLE, we followed a similar approach using RNA sequencing data of monocytes isolated from SLE patients. Notably, we identified an inhibitor of the serine/threonine kinase PIm-1 “SGI-1776” as a promising therapy targeting the Pim-1/NFATc1/NLRP3 pathway. Finally, to expedite LN research, we manually curated the literature for mechanistic molecular interactions associated with LN and depicted them in a disease map, thus creating the Lupus Nephritis map (LNmap). Currently, the map lists 164 publications in the database describing interactions between and within 9 cell types, namely mesangial cells, podocytes, CD4+ T-cells, CD8+ T-cells, B-cells, dendritic cells, monocytes, macrophages and neutrophils. The map is planned to be released to its end-users promptly and is under ongoing development to expand and refine the provided information and increase its reliability and impact on LN research.
Keywords:
LncRNA, Systemic lupus erythematosus, Biomarkers, Bioinformatics, So equencing
