Joanne Aiko Matsubara

Professor

Research Interests

neuroscience
vision
cell and development
cell death pathways
innate immune response
eye disease, retinal degenerations
Alzheimer's disease
neurodegeneration

Relevant Degree Programs

Affiliations to Research Centres, Institutes & Clusters

Research Options

I am available and interested in collaborations (e.g. clusters, grants).
I am interested in and conduct interdisciplinary research.
I am interested in working with undergraduate students on research projects.
 
 

Research Methodology

ocular drug delivery
ophthalmic imaging
Animal models
cell culture models
protein assays
anti-inflammatory therapeutics
inhibitors of complement cascade
models of neovascularization

Recruitment

Master's students
Doctoral students
Postdoctoral Fellows
Any time / year round

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Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - May 2021)
NLRP3 inflammasome activity in RPE: role in AMD pathogenesis (2017)

Purpose:Age-related macular degeneration (AMD) is a devastating eye disease causing irreversible vision loss in the elderly. Retinal pigment epithelium (RPE), an important cell type afflicted in AMD, undergoes cell death in the late stages of the disease. Salient factors underlying AMD pathogenesis are aging, drusen components and NLRP3 inflammasome activity. The purpose of this dissertation is to elucidate the molecular interactions among these factors and how they contribute to RPE damage.Methods:The effects of aging on drusen components, in particular the membrane attack complex (MAC) and amyloid beta (Aβ) were examined in rats at different age. To determine the role of MAC in inflammasome activation in RPE, aurin tricarboxylic acid complex (ATAC), was administrated to naïve rats. To understand Aβ’s role in inflammasome activation, Aβ intravitreal injections were made into rat eyes in vivo and Vinpocetine was used to ameliorate the inflammatory responses. An in vitro RPE cell culture model was established to further investigate the relationship between inflammasome and X-chromosome linked inhibitor of apoptosis (XIAP). Statistical significance was set at p ≤ 0.05.Results:An age-dependent increase in MAC, Aβ, and NF-κB activation was observed in the RPE-choroid in vivo. Blocking MAC formation with ATAC led to a prominent reduction in inflammasome activity (caspase-1 cleavage and cytokine secretion), but not in NF-κB activity. Aβ intravitreal injections triggered inflammasome activation evidenced by enhanced caspase-1 cleavage and IL-1β/IL-18 release, which was suppressed by Vinpocetine mediated NF-κB inhibition. The robust inflammasome activity further led to gasdermin D-mediated activation of the pyroptotic pathway and a significant reduction in XIAP, which in turn enhanced IL-18 secretion.Conclusion:Aging is a strong risk factor for AMD, which increases the deposition of MAC and Aβ in the outer retina. The elevated levels of MAC and Aβ are triggers for inflammasome activation. By demonstrating a causal relationship between inflammasome activation and XIAP reduction, this dissertation suggests the precise regulation of XIAP, together with the suppression of MAC and NF-κB, may be crucial for controlling inflammasome activity and hence provides new avenues to prevent AMD.

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Ocular tissue engineering - rebuilding the retina with stem cells (2017)

The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.

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The Role of Complement Activation in Age-related Macular Degeneration (2016)

Purpose:Age-related macular degeneration (AMD) is a multifactorial degenerative disease that occurs in the central part of the retina − macula. The disease affects approximately one million Canadians and constitutes the number one cause of vision loss after cataract in the elderly. The Y402H polymorphism in the complement factor H (CFH) gene and drusen load are two salient risk factors for AMD. Little is known of the detailed cellular pathway(s) shared by these two factors. Here we investigate their interactions in in vitro models of AMD and in AMD samples. Methods:The biological samples came from 44 dry AMD patients, 23 postmortem eyes and retinal pigment epithelial (RPE) cell models. Drusen load and choroidal thickness in patients were measured using spectral-domain optical coherence tomography. We used analytical techniques including genotyping, Bio-Plex suspension assays, immunohistochemistry, immunofluorescence, reverse transcription PCR, Western blot, flow cytometry and lactate dehydrogenase assay Results:In dry AMD patients, higher systemic levels of interleukin (IL)-6, IL-18, and tumor necrosis factor (TNF)-α were associated with the at-risk CC variant of CFH Y402H polymorphism. IL-1β while not significant, demonstrated a similar trend. Drusen load was inversely correlated with choroidal thickness and visual acuity. Postmortem eyes genotyped with the Y402H risk variant showed significantly increased levels of GM-CSF in vitreous and immunoreactivity for CD68, C5a, IL-18 and TNF-α in Bruch’s membrane and/or choroid. Exposure to complement activation product C5a in RPE cells promoted NF-κB activation and upregulated inflammatory cytokines and growth factors. The drusen component, Aβ, induced complement activation and downregulated the membrane bound complement inhibitor, CD55, leading to sublytic MAC formation in RPE cells, which was inhibited by aurin tricarboxylic acid complex. Conclusion: Two important risk factors for AMD, CFH Y402H polymorphism and drusen load, both promote complement activation. Complement activation can mediate downstream events associated with sublytic changes in RPE, such as proinflammatory cytokine release. These results suggest that complement activation might be the central response to multiple risk factors and the complement activation products may further inflict injury on RPE cells. Complement activation products could be potential therapeutic targets to stop chronic inflammation in AMD.

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Master's Student Supervision (2010 - 2020)
NLRP3 inflammasome contributes to retinal ganglion cell (RGC) death in the DBA/2J mouse model of glaucoma (2020)

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.

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Role of extracellular granzyme B (GzmB) in the disruption of the outer blood-retina barrier (oBRB) and remodeling of Bruch’s membrane (BM) (2020)

Age-related macular degeneration (AMD) is a poorly understood chronic inflammatory eye disease, which is characterized by the atrophy of retinal pigment epithelium (RPE) and the breakdown of Bruch’s membrane (BM), often leading to the formation of choroidal neovascularization (CNV), a hallmark of the exudative form of AMD. Currently, the effective treatments are anti-vascular endothelial growth factor (VEGF) therapies targeting CNV growth. Few studies have been conducted to explore the functions of Granzyme B (GzmB) in AMD. GzmB is a serine protease, stored in the granules of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), and also expressed by different immune and non-immune cells. It was initially believed to be involved in immune-targeted cell death, and recently many studies have revealed an additional role and an extracellular function in several chronic inflammatory disorders, such as asthma, multiple sclerosis (MS), and rheumatoid arthritis (RA). Whether extracellular GzmB activity is involved in the pathogenesis of AMD, a chronic inflammatory disease of the eye, is still not known. This present study hypothesized that extracellular GzmB may affect the function of the outer blood-retina barrier (oBRB) and BM remodeling by cleaving potential substrates in the outer retina. In order to test this hypothesis, this study used immunohistochemistry (IHC) to identify increased numbers of GzmB+ choroidal cells in aged and CNV human ocular tissues, most of which were confirmed to be choroidal mast cells. RPE cells were also found to be another source of GzmB in the outer retina. This study then used cell culture methods and immunocytochemistry (ICC) and western blot to show that exogenous GzmB cleaves RPE cell-cell adhesion proteins (ZO-1, JAM-A, occludin) and RPE-derived extracellular matrix (ECM) substrates (fibronectin, laminin), leading to damaged RPE barrier function and the degradation of ECM components in BM in vitro. These results support the hypothesis that extracellular GzmB may play a role in disrupting the oBRB function and BM remodeling. This study is the first to explore such pathophysiological implications of extracellular GzmB activity in AMD.

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