Unit:
Τομέας ΠαθολογίαςLibrary of the School of Health Sciences
Dissertation committee:
Ορφανός Στυλιανός, Καθηγητής, Ιατρική, ΕΚΠΑ
Κοτανίδου Αναστασία, Καθηγήτρια, Ιατρική, ΕΚΠΑ
Ρούτση Χριστίνα, Καθηγήτρια, Ιατρική, ΕΚΠΑ
Ροβίνα Νικολέττα, Επίκουρη Καθηγήτρια, Ιατρική, ΕΚΠΑ
Βασιλειάδης Ιωάννης, Επίκουρος Καθηγητής, Ιατρική, ΕΚΠΑ
Αϊδίνης Βασίλης, Ερευνητής Α', Ε.ΚΕ.Β.Ε. "Αλέξανδρος Φλέμινγκ"
Δημοπούλου Ιωάννα Μαρία, Καθηγήτρια, Ιατρική, ΕΚΠΑ
Original Title:
Η διερεύνηση του ρόλου της αυτοταξίνης (ΑΤΧ) στην ενήλικη φυσιολογία και τη συστεμική φλεγμονή
Translated title:
Investigating the role of autotaxin (ATX) in adult physiology and systemic inflammation
Summary:
Autotaxin (ATX, Enpp2) is a secreted lysophospholipase D widely present in biological fluids including blood. ATX is the major enzyme catalysing the production of lysophosphatidic acid (LPA) by hydrolysis of lysophosphatidylcholine (LPC), a cell membrane component. LPA is a bioactive, growth factor-like lysophospholipid promoting a large variety of cellular responses in almost all cell types, mediated from at least six G-protein coupled LPA receptors (LPARs) that exhibit overlapping specificities and widespread distribution. ATX expression and LPA production were shown to be necessary for embryonic development, as ubiquitous genetic deletion of ATX resulted to vascular and neuronal defects leading to lethality. In adult life, ATX is widely expressed and upregulated levels have been reported in various chronic inflammatory diseases and cancer. Conditional genetic deletion of ATX attenuated the development of rheumatoid arthritis, pulmonary fibrosis and hepatocellular carcinoma in mouse models, suggesting a primary role in disease pathogenesis. Taking into account the involvement of ΑΤΧ/LPA signaling in various pathological conditions, ATX has emerged as a promising therapeutic target in chronic inflammatory diseases and cancer. As a result, a large number of ATX inhibitors have been developed. Moreover, the crystal structure of ATX was solved enabling rational drug design. Here it is reported that inducible, ubiquitous genetic deletion of ATX in adult mice, as well as its potent pharmacologic inhibition, are well tolerated, alleviating potential toxicity concerns of ATX therapeutic targeting. In more details, genetic ATX ablation appeared to have no major effects neither in the hematopoietic system nor in tissue homeostasis exhibiting no deleterious changes indicative of liver, kidney, or pancreatic function. High dosing of ATX inhibitor for a prolonged period resulted in no weight loss of mice or histopathological changes in 13 major organs examined. As it pertains to the involvement of ATX in the pathogenesis of systemic inflammation, despite a detrimental role of ATX in LPS-induced systemic inflammation, current results were relatively inconclusive, rendering a valid conclusion unsafe, reflecting the complexity of sepsis.
Main subject category:
Health Sciences
Keywords:
Autotaxin (ATX, Lysophosphatidic Acid (LPA), Adult Physiology, Systemic Inflammation
Number of references:
437
