Project I: Mechanisms regulating contribution of pericytes to brain repair after stroke

Description: Stroke constitutes a major public health problem in Canada. No definite therapies exist yet to completely restore the lost brain functions. Nonetheless, there is convincing evidence that the brain possesses an intrinsic ability to repair itself and partially regenerate in order to functionally recover. Indeed, stroke triggers emergence of diverse restorative processes that include neurogenesis, neuronal remodelling and angiogenesis. Nonetheless, these processes are limited and not fully sufficient to efficiently restore neurological functions. It is now clear that in order to strengthen functional recovery after stroke, the brain needs assistance to reinforce its intrinsic ability to repair itself. Pericytes are master regulators of vascular homeostasis, and have as well pleiotropic functions ranging from stromal to plastic properties. Stroke induces pericyte activation translated by profound functional changes that include proliferation, migration as well as enhanced plasticity. Emerging evidence suggests that activated pericytes contribute to brain repair after stroke via as-yet poorly understood mechanisms. Due to their multitasking characteristics, pericytes constitute intriguing targets in stroke therapies. Our investigations suggest that activation of hypoxia-inducible factors (HIFs) after stroke primes the pericytes to generate reparative and regenerative functions via induction of the transcription factor Kruppel-like factor-4 (KLF4). The project aims to elucidate the role of HIFs-KLF4 crosstalk in regulating pericytes activation, and explore the potential of HIFs/KLF4-primed pericytes in promoting recovery after stroke. The project’s long-term goal is to harness pericyte plasticity for developing novel cell-based therapies. *Funded by the Canadian Institutes of Health Research (CIHR)

Project II: Neurovascular Restoration in Stroke: Role of Dickkopf-Related Protein-1 (DKK1)

Description: The neurovascular unit emerged as a novel concept integrating the interactions between the vascular, neuronal and glial cells that work in concert to enable the proper functioning of the brain. The concept provided new perspectives to develop new stroke therapies that go beyond targeting the intra-neuronal death mechanisms. Disruption of the neurovascular interactions hampers brain regeneration after stroke. Our proof-of-concept investigations show that the evolutionary conserved canonical wingless-type (Wnt) pathway, which plays major roles in neurovascular development, is deregulated after stroke. The project proposes a novel therapeutic approach involving neurovascular repair via activation of the pathway in an acute and sub-acute settings to improve thrombolysis and promote neurorestoration. Deregulation of the delicate DKK1/Wnt balance after ischemic stroke hampers the endogenous regenerative capabilities of the brain. Accordingly, the project postulates that promotion of the neurovascular repair via inhibition of the DKK1, which negatively regulates the intrinsic regenerative properties of the canonical Wnt pathway, holds promise to boost the endogenous regenerative capabilities of the brain. DKK1 inhibition aims to achieve two major goals; (a) improve tPA-induced thrombolysis in the acute phase, and (b) stimulate neurorestoration in the sub-acute phase. As DKK1 is induced specifically by ischemic insult, its inhibition constitutes an elegant approach to activate the pathway specifically in the affected tissue. *Funded by Heart and Stroke Fondation of Canada (HSFC)

Project III: Role of canonical Wnt pathway in regulating the structural and functional integrity of the blood-brain barrier in the normal adult brain

Description: Maintaining homeostasis of the brain microenvironment is crucial for proper functioning of the brain. Brain homoeostasis depends upon the blood-brain barrier (BBB), which lines the lumen of cerebral endothelium formed by endothelial cells. Little is known about the molecular mechanisms controlling the physiological function of the BBB in the adult brain throughout lifespan. The canonical wingless-type (Wnt) pathway has been shown to control the formation and maturation of the BBB during ontogeny. Until recently, it was thought that after birth the pathway is quiescent in the adult brain. Although the recent findings suggest that the canonical Wnt pathway contributes to neurogenesis and synaptic plasticity in the adult brain, whether the pathway regulates the physiological function of the BBB in the adult brain remains totally elusive. Our investigations suggest that the canonical Wnt pathway is still required to maintain brain homeostasis via the BBB and it is physiologically regulated by the human variant E4 of apolipoprotein E (ApoE4). The main objectives of my research program are to address the following questions: (i) how the process of normal ageing influences regulation of the canonical Wnt pathway at the BBB, (ii) whether the pathway is required to maintain BBB properties in the adult brain, and (iii) how ApoE polymorphism affects BBB physiological function via the canonical Wnt pathway. *Funded by the Natural Sciences and Engineering Research Council of Canada (NSERC)

Project IV: The role of apolipoprotein E4-canonical Wnt pathway crosstalk at the blood-brain barrier in Alzheimer’s disease

Description: Alzheimer’s disease (AD) is a progressive neurological disorder that causes the degeneration of brain’s nerve cells. Historically, research in the field emphasized on studying brain’s nerve cells. Recently, it was demonstrated that destabilization of the cerebral blood vessels, which decisively supports the survival of brain’s nerve cells, causatively contributes to AD initiation and progression. The destabilized cerebral blood vessels deprive the brain from nutrients, and alter the removal of toxic amyloid-beta (Aβ) peptides leading to its aggregation, which constitute with tau protein aggregation the main pathological hallmarks of AD. The mechanisms underlying cerebral blood vessels destabilization are not fully characterized. Recent reports have demonstrated that the apolipoprotein E gene variant ɛ4 (ApoEɛ4), which constitute the main genetic risk factor for AD, destabilizes the cerebral blood vessels via non-identified mechanism. Our findings suggest that the pathway is progressively deactivated during ageing – a major risk factor for AD – in a mouse model for AD. Furthermore, we found that ApoEɛ4 specifically deactivates the pathway in cells that from the cerebral blood vessels. Importantly, pathway deactivation positively correlates with the duration of symptoms and is exacerbated in patients carrying ApoEɛ4. As such, the project aims to, a) assess whether ApoEɛ4 destabilizes the cerebral blood vessels by specifically deactivating the canonical Wnt pathway, and b) test whether restoration of the cerebral blood vessels stability via canonical Wnt pathway activation attenuates AD progression and whether ApoEɛ4 can affect this process.*Funded by Scottish Rite Charitable Foundation of Canada (SRCFC)

Project V: Activation of canonical Wnt pathway as a new therapy for ischemic stroke

Description: Blood-brain barrier (BBB) breakdown following ischemic stroke increases brain injury, which can be exacerbated by recombinant tissue-plasminogen activator (rtPA)-induced thrombolysis. The Wnt/β-catenin pathway is deactivated at the BBB following ischemic stroke. We postulate that BBB breakdown, secondary to Wnt/β-catenin pathway deactivation, contributes to ischemic stroke pathobiology. Accordingly, pathway activation constitutes an elegant therapeutic approach to extend rtPA therapeutic window, prevent rtPA-associated complications and promote neurorestoration by specifically stimulating BBB repair. The project aims to to decipher the molecular and functional regulation of the BBB by Wnt/β-catenin pathway following ischemic stroke, and to test the efficacy of Wnt/β-catenin pathway activation in enhancing thrombolytic therapy and promoting neurorestoration by stimulating BBB repair following ischemic stroke. *Funded by the grant program of Faculty of Medicine of Université Laval-Merck Sharp & Dohme

Project VI: Signalisation de l’unité neurovasculaire suite aux maladies cérébrovasculaires: Implications pathobiologiques et thérapeutiques

Description: It is an establishment grant supporting a research program aims at deciphering the molecular and cellular mechanisms underlying vascular cell dysfunction following stroke in order to develop new therapeutic interventions that focus on restoring the homeostasis of the neurovascular unit and consequently promote tissue repair after stroke.*Funded by the Fonds de recherche du Québec – Santé (FRQS)

Project VII: Laboratory of inter-cellular dynamics within the neurovascular unit in cerebrovascular diseases

Description: it is an infrastructure grant that aims at acquiring new infrastructure to investigate the functional remodelling of neurovascular interactions in cerebrovasculare diseases. *Funded by Canada Foundation for Innovation (FCI)

Complete profile at Vice-rectorat à la recherche et à la création of Université Laval: http://www.vrrc.ulaval.ca/fileadmin/ulaval_ca/Images/recherche/bd/chercheur/fiche/6017942.html

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