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DTSTAMP:20260424T143242Z
UID:1756728000@ist.ac.at
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DESCRIPTION:Speaker: Florianne Miteva\nhosted by Alicia Michael\nAbstract: 
 Prostaglandins play a central role in the inflammatory response. Prostagla
 ndins are synthesized in a rate-limiting manner by the enzyme cyclooxygena
 se (Cox)\, which exists in two isoforms: the Cox-2 and Cox-1 isoforms. Tra
 ditionally\, Cox-1 is thought to mediate homeostatic functions due to its 
 constitutive expression due to its constitutive expression\, whereas Cox-2
  is temporary induced in response to inflammatory stimuli and is associate
 d with the the inflammatory response. Interestingly\, in the central nervo
 us system\, Cox-1 is predominantly expressed in microglia. As the resident
  immune cells of the brain\, microglia play a key role in inflammation. Co
 x-1 expressing microglia are increased in neurodegenerative diseases\, and
  both global knockout of Cox-1 and selective Cox-1 inhibition has been sho
 wn to ameliorate inflammatory effects in neurodegenerative diseases. Howev
 er\, direct evidence elucidating how microglial Cox-1 expression influence
 s their response to insults remains limited and warrants further investiga
 tion.First\, I utilize the optic nerve crush (ONC) model to study the micr
 oglial response to injury and inflammation\, confirming a reactive microgl
 ial response in both the crushed and uninjured contralateral retina using 
 CD68 expression and morphological analysis. While previous studies reporte
 d retinal ganglion cell (RGC) loss in the contralateral eye\, I did not ob
 serve this\, suggesting that unilateral ONC induces microglial activation 
 in the contralateral eye without RGC degeneration. To explore the role of 
 Cox-1 in this response\, I generated a mouse model with microglia-specific
  deletion of Cox-1. After ONC\, these mice exhibited an attenuated microgl
 ial response in both the ipsilateral and contralateral retinas\, as well a
 s in visual processing areas of the brain. Notably\, Cox-2 does not show a
 ny expression after ONC in both wild-type and Cox-1 knockout mice Addition
 ally\, Cox-1KO mice show a reduction in phagocytic cups and a reduction in
  microglia proliferation after ONC. However\, due to reproducibility probl
 ems of the observed phenotype\, even after the generation of two new mouse
  models\, I cannot draw any definitive conclusions based on the data.Next\
 , due to the ambiguity of the mouse model\, I explored an alternative rout
 e to investigate functional consequences of Cox-1 in microglia. I generate
 d a COX1 knock-out human induced pluripotent cell (hIPSC) line using CRISP
 R/Cas9. These cells are were differentiated in microglia-like cells and in
 tegrated in dissociated retinal organoids according to protocols developed
  in our lab. In response to LPS and Poly (I:C) stimulation\, the release a
 nd expression of cytokines and chemokines was decreased in COX1 knockout c
 ells. However\, the prostaglandin PGE2 was not increased in micorglia-like
  cells in both control and COX1 knockout cells.Overall\, the results from 
 the COX1 knock-out microglia-like cells suggests that COX1 expression in m
 icroglia play a role in neuroinflammation by affecting the release of infl
 ammatory cytokines and chemokines. Hereby further challenging that the dog
 ma of the Cox-1 isoform involved in housekeeping functions and the Cox-2 i
 soform involved in inflammation applies for the central nervous system.
LOCATION:Central Bldg / O1 / Mondi 2b (I01.O1.008) and Zoom\, ISTA
ORGANIZER:
SUMMARY:Florianne Miteva: Thesis Defense: The role of cyclooxygenase 1 on m
 icroglial response to inflammatory stressors
URL:https://talks-calendar.ista.ac.at/events/5956
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