NLRP3 inflammasome contributes to retinal ganglion cell (RGC) death in the DBA/2J mouse model of glaucoma
department or school: Medicine, Faculty of
data provider: DSpace
degree campus: UBCV
creator: Li, Siqi
issued: 2020-09-11T20:05:59Z
issued: 2020
related degree: Master of Science - MSc
degree grantor: University of British Columbia
description: Glaucoma is a neurodegenerative eye disease characterized by elevated intraocular pressure (IOP) in the majority of cases, followed by retinal ganglion cell (RGC) loss. Neuroinflammation is an important factor contributing to RGC death during glaucoma pathogenesis. Evidence suggests that NLRP3 (nucleotide-binding oligomerization domain (NOD)-like receptor protein 3) inflammasome activity is associated with IOP-induced RGC death. To investigate whether NLRP3 inflammasome is activated by IOP elevation, the DBA/2J mouse model of glaucoma with age-related IOP elevation was studied. Female mice were sacrificed at 3 or 9 months of age. IOP was measured before sacrifice. NLRP3 inflammasome related proteins and RGC loss were quantified in eye tissues. To further assess whether NLRP3 inflammasome activation contributes to RGC death, mice were treated with 8 weeks of daily oral administration of 30 mg/kg MCC950, a specific small-molecule drug that prevents NLRP3 inflammasome activation. In the 9-month DBA/2J mice, IOP was significantly increased compared to 3-month mice. Concomitantly, protein levels of NLRP3 and cleaved caspase-1 were significantly higher in 9- month DBA/2J. The plasma level of circulating MCC950 (7650±775.3 ng/ml) after 8 weeks of drug administration was above the efficacy threshold (>1000 ng/ml). The MCC950 treated mice retained a higher number of surviving RGCs, exhibited lower levels of NLRP3 expression and caspase-1 cleavage compared to age-matched controls. In this study, we discovered MCC950 treatment inhibits the age-related increase of NLRP3 inflammasome activity and ameliorates RGC loss, suggesting that NLRP3 inflammasome activation is associated with RGC death in this mouse model.
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/75981
note: NLRP3 INFLAMMASOME CONTRIBUTES TO RETINAL GANGLION CELL (RGC) DEATH IN THE DBA/2J MOUSE MODEL OF GLAUCOMA by Siqi Li B.Sc, Zhejiang University, 2017 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in The Faculty of Graduate and Postdoctoral Studies (Cell and Developmental Biology) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) September 2020 ©Siqi Li, 2020 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, a thesis entitled: NLRP3 INFLAMMASOME CONTRIBUTES TO RETINAL GANGLION CELL (RGC) DEATH IN THE DBA/2J MOUSE MODEL OF GLAUCOMA submitted by Siqi Li in partial fulfillment of the requirements for the degree of Master of Science in Cell and Developmental Biology Examining Committee: Joanne Matsubara, Cell and Developmental Biology Supervisor Orson Moritz, Cell and Developmental Biology Supervisory Committee Member Tim O’Connor, Cell and Developmental Biology Supervisory Committee Member Deborah Giaschi, Department of Ophthalmology and Visual Sciences Additional Examiner Additional Supervisory Committee Members: Elizabeth Simpson, Department of Medical Genetics Supervisory Committee Member iii Abstract Glaucoma is a neurodegenerative eye disease characterized by elevated intraocular pressure (IOP) in the majority of cases, followed by retinal ganglion cell (RGC) loss. Neuroinflammation is an important factor contributing to RGC death during glaucoma pathogenesis. Evidence suggests that NLRP3 (nucleotide-binding oligomerization domain (NOD)-like receptor protein 3) inflammasome activity is associated with IOP-induced RGC death. To investigate whether NLRP3 inflammasome is activated by IOP elevation, the DBA/2J mouse model of glaucoma with age-related IOP elevation was studied. Female mice were sacrificed at 3 or 9 months of age. IOP was measured before sacrifice. NLRP3 inflammasome related proteins and RGC loss were quantified in eye…
has type: Thesis/Dissertation
date issued: 2020-11
is shown at: 10.14288/1.0394326
language: eng
degree discipline: Cell and Developmental Biology
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/75981