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https://hdl.handle.net/123456789/40| Τύπος: | Διδακτορική διατριβή |
| Τίτλος: | Αλληλούχιση του RNA και ανάλυση της γονιδιακής έκφρασης των αιμοποιητικών στελεχιαίων κυττάρων στον Συστηματικό Ερυθηματώδη Λύκο |
| Εναλλακτικός τίτλος: | RNA-sequencing and transcriptome analysis of hematopoietic stem cells in Systemic Lupus Erythematosus |
| Συγγραφέας: | [EL] Γρηγορίου, Μαρία[EN] Grigoriou, Maria |
| Επιβλέπων διατριβής: | [EL] Μπούμπας, Δημήτριος[EN] Boumpas, Dimitrios |
| Μέλος εξεταστικής επιτροπής: | [EL] Μπερτσιάς, Γεώργιος[EN] Bertsias, George [EL] Βασιλόπουλος, Δημήτριος[EN] Vasilopoulos, Dimitrios [EL] Ρουμπελάκη, Μαρία[EN] Roubelakis, Maria [EL] Νικολάου, Χριστόφορος[EN] Nikolaou, Christoforos [EL] Βεργίνης, Παναγιώτης[EN] Verginis, Panayotis [EL] Μητρούλης, Ιωάννης[EN] Mitroulis, Ioannis |
| Ημερομηνία: | Οκτ-2019 |
| Περίληψη: | Systemic Lupus Erythematosus (SLE) is a prototypic autoimmune disease that affects mainly women and typically exhibits manifestations in multiple organs including skin, joints, kidneys and nervous system. It is a complex disease resulting from the interaction of heritable (genetic and epigenetic), hormonal and environmental factors. Immune complexes, auto-antibodies and all blood cells (auto-reactive lymphocytes, dendritic cells, etc) are involved in clinical manifestations. Hematopoietic Stem and Progenitor Cells (HSPCs) are multipotent cells giving rise to all blood cell lineages, both myeloid and lymphoid. We reasoned that the aberrancies of immune cells observed in SLE could be traced back to HSPCs. The aim of the study is to further investigate the role and function of bone marrow-derived HSPCs in SLE. Bone marrow (BM) samples from female NBZW/F1 lupus-prone mice and their age-matched controls were used. HSPCs defined as Lin-Sca-1+c-Kit+ hematopoietic progenitors (LSK). Transcriptomic analysis of LSK from diseased lupus mice demonstrated a strong myeloid signature accompanied with expanded frequencies of common myeloid progenitors (CMPs) -but not of common lymphoid progenitors (CLPs)- reminiscent of a “trained immunity” signature. CMP profiling revealed an intense transcriptome reprogramming with suppression of granulocytic regulators as major regulators such as Cebpe, Cebpd and Csf3r are downregulated in lupus mice. The data are indicative of a differentiation arrest and disturbed myelopoiesis. Despite the differentiation arrest, frequencies of BM neutrophils were markedly increased in diseased mice suggesting an alternative granulopoiesis pathway. In humans, hematopoietic progenitors were defined and isolated as CD34+ BM cells. In SLE patients with severe disease pattern, CD34+ demonstrated enhanced proliferation, cell differentiation and transcriptional activation of cytokines and chemokines that drive differentiation towards myelopoiesis thus mirroring the murine data. Comparative analysis of human and murine transcriptional profiles revealed that murine CMP and human CD34+ cells shared an attenuated myeloid signature consistent with a differentiation arrest. Collectively, these data demonstrate priming of HSPCs and aberrant regulation of myelopoiesis in SLE, potentially contributing to persistent inflammation and risk for flare. The data point out the crucial role of BM homeostasis in SLE pathogenesis therefore the construction of in vitro BM simulating system is emerging. This system will provide easily further mechanistic and functional investigation with fewer samples from animal models and human samples. |
| Γλώσσα: | Ελληνικά; Αγγλικά |
| Τόπος δημοσίευσης: | Αθήνα, Ελλάδα; Athens, Greece |
| Σελίδες: | 108 |
| Θεματική κατηγορία: | [EL] Ιατρική και Επιστήμες Υγείας[EN] Medical and Health Sciences |
| Λέξεις-κλειδιά: | Αυτοανοσία; Συστηματικός Ερυθηματώδης Λύκος; Αιμοποίηση; Αρχέγονα αιμοποιητικά κύτταρα; Μεταγράφωμα |
| Κάτοχος πνευματικών δικαιωμάτων: | Μαρία Γρηγορίου |
| Διατίθεται ανοιχτά στην τοποθεσία: | https://www.didaktorika.gr/eadd/handle/10442/46791 |
| Σημειώσεις: | The present study was done at the Biomedical Research Foundation of the Academy
of Athens . This work was supported by: 1. Greece and the European Union (European Social Fund-ESF) through the Operational Programme «Human Resources Development, Education and Lifelong Learning» in the context of the project “Strengthening Human Resources Research Potential via Doctorate Research” (MIS-5000432), implemented by the State Scholarships Foundation (ΙΚΥ), 2. a research grant from FOREUM Foundation for Research in Rheumatology, 3. a research grant from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 742390). |
| Εμφανίζεται στις συλλογές: | Υποψήφιοι διδάκτορες |
Αρχεία σε αυτό το τεκμήριο:
| Αρχείο | Περιγραφή | Σελίδες | Μέγεθος | Μορφότυπος | Έκδοση | Άδεια | |
|---|---|---|---|---|---|---|---|
| PhD thesis_GrigoriouMaria.pdf | 9.39 MB | Adobe PDF | - |  | Δείτε/ανοίξτε |