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G+PS regularly provides virtual sessions that focus on admission requirements and procedures and tips how to improve your application.
Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - Nov 2019)
Marfan syndrome (MFS), a connective tissue disorder triggered by mutations in Fibrillin-1, causes life-threatening pathology including aortic aneurysm. Recently, controversy has arisen regarding the use of anti-hypertensive angiotensin-II (AngII) receptor type 1 (ATR1) blocker losartan in MFS as, despite success in animal models, losartan has failed to show superiority over standard β-adrenergic receptor blocker atenolol in preventing or slowing expansion of aortic root aneurysm in MFS patients. Overall, we hypothesized that we could provide new insight into this controversy via development of a novel MFS murine model lacking functional ATR1 signaling. Herein, using this novel model, we demonstrate that MFS aortic, pulmonary and skeletal pathology as well as the therapeutic benefit of losartan in MFS aneurysm prevention are ATR1-independent. Instead, we reveal the primary therapeutic pathway of losartan in MFS to be nitric oxide synthase (NOS)-dependent, as treatment of MFS aneurysm in vivo has no benefit upon inhibition of NOS. Furthermore, losartan is shown to mediate increased NO release in endothelial cells in the absence of AngII and correct NO levels in the plasma of MFS mice. In addition, declining plasma nitric oxide (NO) levels in mice were found to correlate to increasing aortic aneurysm size and sub-analysis of patients treated with losartan shows indices of improved endothelial function to correlate to regression of aortic aneurysm. Finally, we demonstrate the clinical potential of targeting endothelial dysfunction in MFS as murine models of endothelial nitric oxide synthase (eNOS) over-expression and hyper-activation as well as pharmacological activation of endogenous eNOS all result in prevention of MFS aneurysm. Overall, this study is the first to identify key aspects of MFS pathology and treatment including the ATR1-independent nature of MFS aortic, lung, and skeletal pathology and therapeutic benefit of losartan. Moreover, these studies are the first to show a NOS-dependent mechanism of losartan and therapeutic benefit of increasing NO bioavailability and improving endothelial function in MFS. As such, they collectively provide a basis for guiding the evolution of managing and treating MFS as well as future pharmaceutical development.
Cardiovascular diseases are one of the largest causes of mortality globally. One of the hallmarks of cardiovascular diseases is a reduction in systemic endothelial nitric oxide synthase (eNOS)-derived Nitric Oxide (NO), a critical regulator of vascular homeostasis. eNOS regulation is complex, involving phosphorylation and direct protein interactions. The main negative regulator is caveolin-1 (Cav-1), the homo-oligomeric coat protein of caveolae, which interacts with eNOS via its scaffolding domain (CAV). Studies have shown that alanine substitution of F92 in CAV can lead to abolishment of the inhibitory effect on eNOS; furthermore, CAV peptides with the F92A substitution can be used as an antagonist to promote basal eNOS-derived NO to reduce blood pressure and reduce cardiovascular disease progression. We hypothesized that identification of the eNOS binding motif in CAV could be used as the basis for a pharmacophore to develop antagonists aimed at increasing vascular NO. We performed a protein interaction study to identify a 10 residue ‘binding site peptide’ (BSP) in CAV that could account for the majority of eNOS binding. Both BSP and its F92A counterpart (BSPF92A) bound eNOS with similar affinity as the full CAV sequence as confirmed by polarization assay, while computational modeling suggested that the peptides inserted themselves in to a hydrophobic pocket in eNOS.While substitution of F92 prevents inhibition of activated eNOS, we found that both BSP and BSPF92A could promote basal NO release from resting endothelial cells (ECs), independent of cell permeabilization sequence used. Furthermore, BSP and BSPF92A generated NO in an eNOS and lipid raft dependent manner. Subsequently, we found that neither BSP nor BSPF92A affected basic biochemical properties of eNOS and Cav-1, such as oligomerization, subcellular targeting and co-localization. Instead, the presence of F92 was found to promote phosphorylation of eNOS, an important step in its activation. As a result of this finding, we have identified the basis for two different pharmacophores that increase NO in different manners. One that promotes activity indirectly (BSP) while the other one acts as an antagonist (BSPF92A). We hope to use this as the beginnings for a therapeutics development platform to promote cardioprotective NO.
No abstract available.
Master's Student Supervision (2010 - 2018)
Nitric Oxide (NO) produced by the endothelium is a critical mediator of vascular function and plays an important role in the protection against various cardiovascular diseases1. In fact, a central feature of most cardiovascular diseases is reduced bioavailability of NO resulting from impaired endothelial function. Consequently, therapies that improve NO synthesis and availability in disease settings are relevant. Endothelial nitric oxide synthase (eNOS) is a membrane enzyme expressed exclusively in vascular endothelial cells and is responsible for NO production. Improper regulation of the enzyme results in production of eNOS-derived superoxide anion (O₂₋) instead of NO. O₂₋ is an oxidative stress mediator and scavenges NO, thereby contributing to lowered NO bioavailability. Extensive research has demonstrated a number of factors involved in positively regulating eNOS activity. However, one of the few proteins that bind to eNOS under basal conditions and inhibit NO release is Caveolin-1 (Cav-1), the major coat protein of plasma membrane lipid-enriched invaginations known as caveolae². Recently, it was demonstrated that a single amino acid substitution of the Cav-1 protein, mutant known as F92A Cav-1, is unable to inhibit eNOS³. Furthermore, preliminary data indicates that high expression of F92A Cav-1 can increase basal NO release. Due to the significance of NO in vascular function, the current work explores the possible mechanisms by which F92A Cav-1 potentiates eNOS activity and NO release. We report that F92A Cav-1 preserves the unique properties of Cav-1, including targeting to caveolae and forming high molecular weight oligomers, which are essential for caveolae organelle biogenesis. Moreover, F92A Cav-1 still retains the ability to bind to eNOS without altering its subcellular localization, indicating that F92A Cav-1 can prevent eNOS binding to endogenous Cav-1, which could rationalize the increased NO release observed. Lastly, we provide evidence that over-expression of F92A Cav-1 reduces the release of basal O₂₋ in endothelial cells as compared to WT Cav-1, revealing another potential positive effect of the mutant Cav-1. Hence, this report compares the biological properties of WT and F92A Cav-1 and the data collected is aimed at describing a therapeutically relevant pharmacological target to increase NO bioavailability in cardiovascular disease settings.
Heart disease and cancer are the two leading causes of death worldwide. In heart disease, reperfusion of an ischemic myocardium through increased angiogenesis, or the growth of new blood vessels, is considered the ‘holy grail’ of future therapies. In contrast, inhibiting tumour growth by decreasing angiogenesis through anti-angiogenic therapies is increasingly used in cancer patients, although the therapeutic effect is only partial. Hence, a better comprehension of angiogenesis is clearly warranted. While a plethora of literature suggests that the vascular endothelial growth factor (VEGF) and angiopoietins systems are the most potent endogenous regulators of angiogenesis, an increasing number of recent studies also show that their net angiogenic effects are mostly dictated by membrane expression of their main receptors, VEGFR-2 and tie-2, respectively. Recently, endothelial cells (ECs) were unexpectedly found to express myoferlin, a muscle protein  known for its ability to regulate plasma membrane integrity . Moreover, myoferlin was found to be involved in the regulation of VEGFR-2 expression in ECs . In this work, we report that disruption of myoferlin by gene-silencing causes decreased tie-2 expression in cultured ECs. However, myoferlin disruption does not affect the transcriptional levels of tie-2 in cultured ECs. Separation of caveolae/lipid rafts from cytosol in ECs shows presence of myoferlin and tie-2 in caveolae/lipid rafts, suggesting co-localization of the two proteins to form a large signaling complex at caveoli, which are known platforms for clustering of signaling complexes. Moreover, myoferlin is present in a cancer cell model (Lewis Lung Carcinoma) and myoferlin disruption causes decreased cell proliferation, further exploring the involvement of this membrane protein in a completely different cell system. The current work identifies potential pharmacological targets for the regulation of the tie-2 system and since tie-2 expression is almost exclusively found in ECs, this work initiates the characterization of an EC-specific target that could be further exploited to modulate angiogenic responses in an in vivo model.