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The role of caveolin-1 in blood-brain barrier repair in stroke and traumatic brain injury: towards a general protective strategy for the neurovascular unit

English title The role of caveolin-1 in blood-brain barrier repair in stroke and traumatic brain injury: towards a general protective strategy for the neurovascular unit
Applicant Hirt Lorenz
Number 163465
Funding scheme Project funding
Research institution Service de Neurologie Département des Neurosciences Cliniques CHUV
Institution of higher education University of Lausanne - LA
Main discipline Neurology, Psychiatry
Start/End 01.05.2016 - 30.06.2020
Approved amount 458'023.00
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All Disciplines (2)

Discipline
Neurology, Psychiatry
Pathophysiology

Keywords (7)

cav-AP; neuroprotection; caveolin; traumatic brain injury; stroke; Blood brain barrier; cerebral ischemia

Lay Summary (French)

Lead
La fonction de l'unité neurovasculaire est importante dans les mécanismes de lésions secondaires après un accident vasculaire cérébral ou un traumatisme cranio-cérébral. La cavéoline-1 (Cav-1) une protéine d'échafaudage ("scaffold protein") exprimée dans les cellules endothéliales. Le but du projet est d'étudier le rôle de Cav-1 et ses interactions avec les voies de JNK et de l’eNOS dans deux modèles expérimentaux en parallèle: un modèle d’AVC chez la souris, au CHUV et un modèle de TCC murin, dans le laboratoire du Pr. Jérôme Badaut, à Bordeaux.
Lay summary

L’accident vasculaire cérébral (AVC) et le traumatisme cranio-cérébral (TCC) sont tous deux des problèmes majeurs de santé publique, avec une mortalité importante et un handicap persistant pour bon nombre de patients.  Malgré des mécanismes primaires très différents, il y a plusieurs points communs dans les mécanismes secondaires tels que la formation d’œdème, les hémorragies, les modifications de flux sanguin et la rupture de la barrière hémato-encéphalique. Les cellules endothéliales des capillaires sanguins cérébraux ont un rôle central dans cette barrière et dans l'unité neurovasculaire. La cavéoline-1 (Cav-1) qui est exprimée dans les cellules endothéliales est une protéine de structure des cavéoles, de petites invaginations de la membrane plasmique. Cav-1 joue en outre un rôle de protéine d’échafaudage (« scaffold protein ») en liant des molécules de signalisation intracellulaire par son domaine CSD (caveolin scaffolding domain) et ainsi en régulant et compartementalisant leurs effets. Cav-1 participe au contrôle de la voie de signalisation de la c-Jun N-terminal kinase (JNK), une kinase intracellulaire impliquée notamment dans la mort cellulaire, et de celle de la NO-synthase endothéliale (eNOS) qui agit sur le débit sanguin cérébral. L’effet de Cav-1 peut être mimé par administration d’un peptide synthétique, Cav-AP combinant le domaine CSD  à une séquence d’internalisation (AP). Nous allons étudier le rôle de Cav-1 et ses interactions avec les voies de JNK et de l’eNOS dans deux modèles expérimentaux en parallèle: un modèle d’AVC chez la souris,  au CHUV et un modèle de TCC, dans le laboratoire du Pr. Jérôme Badaut, à Bordeaux. Notre hypothèse est que l’administration intra-péritonéale de Cav-AP atténuera la formation d’œdème, la mort neuronale et améliorera la récupération fonctionnelle. 

Direct link to Lay Summary Last update: 16.11.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Caveolin-1 Regulates Perivascular Aquaporin-4 Expression After Cerebral Ischemia
Filchenko Irina, Blochet Camille, Buscemi Lara, Price Melanie, Badaut Jerome, Hirt Lorenz (2020), Caveolin-1 Regulates Perivascular Aquaporin-4 Expression After Cerebral Ischemia, in Frontiers in Cell and Developmental Biology, 8, 1-10.
Extended preclinical investigation of lactate for neuroprotection after ischemic stroke
Magistretti Pierre, Lei Hongxia, Hirt Lorenz, Buscemi Lara, Blochet Camille, Price Melanie (2020), Extended preclinical investigation of lactate for neuroprotection after ischemic stroke, in Clinical and translational neuroscience, 4(1), 1-9.
Involvement of caveolin-1 in neurovascular unit remodeling after stroke: Effects on neovascularization and astrogliosis
Blochet Camille, Buscemi Lara, Clément Tifenn, Gehri Sabrina, Badaut Jérôme, Hirt Lorenz (2020), Involvement of caveolin-1 in neurovascular unit remodeling after stroke: Effects on neovascularization and astrogliosis, in Journal of Cerebral Blood Flow & Metabolism, 40(1), 163-176.
Increase of aquaporin 9 expression in astrocytes participates in astrogliosis
Hirt Lorenz, Price Melanie, Mastour Nabil, Brunet Jean-François, Barrière Grégory, Friscourt Frédéric, Badaut Jerome (2018), Increase of aquaporin 9 expression in astrocytes participates in astrogliosis, in Journal of Neuroscience Research, 96(2), 194-206.
Aquaporins in neurological disorders
Hirt Lorenz, Price Melanie, Benakis Corinne, Badaut Jerome (2018), Aquaporins in neurological disorders, in Clinical and translational neuroscience, 2(1), 1-7.

Collaboration

Group / person Country
Types of collaboration
Group Professor Rolf Gruetter, CIBM Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Jerome Badaut France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Associated projects

Number Title Start Funding scheme
170155 Novel theranostic approaches for stroke based on hyperpolarized Magnetic Resonance Imaging 01.09.2017 Project funding

Abstract

1 Summary of research planBrain ischemia and traumatic brain injury (TBI) are major public health issues that result in significant mortality and long-term morbidity among survivors. Despite differences in the primary injuries, stroke and TBI share similar secondary events, including haemorrhage, cerebral blood flow (CBF) changes, blood-brain barrier (BBB) breakdown, oedema formation and neuronal death. To date, treatment strategies targeting neuronal rescue after stroke and TBI have not been clinically successful. The neurovascular unit (NVU) has not received enough attention and we propose that treatments targeting the NVU are needed both for stroke and TBI patients and are critical for restoring post-injury CBF, BBB functions and behavioural outcome. Studying in parallel two distinct brain injury models has the unique potential to identify critical common mechanisms of damage of the NVU. Caveolin-1 (Cav-1), a vascular structural protein involved in caveolae formation, cell signalling and BBB permeability is found in the brain, predominantly in endothelial cells. Cav-1 expression is regulated after stroke and was proposed to be beneficial in post-stroke BBB recovery by limiting nitric oxide production (NO), inhibiting reactive oxygen species (ROS) and MMP activity after injury. In addition to its role as a structural protein in caveolae, Cav-1 also acts as a scaffolding protein through a sequence of 19 amino acids named the caveolin scaffolding domain (CSD) to compartmentalize signalling molecules, including endothelial nitric oxide synthase (eNOS) and c-Jun N-terminal kinase (JNK). Caveolin-1 has been shown to bind and inhibit eNOS activity and modulates JNK activity in endothelial cells in the systemic vascular system. A synthetic peptide of the CSD, fused to the Antennapedia (AP) internalization sequence to facilitate cellular penetration, is available (Cav-AP) and reproduces endogenous CSD function such as binding and inhibiting eNOS, and is now in development for human cancer treatment. However, little is known about the role of cav-1 in vascular disease; and its role in BBB recovery has never been investigated using cav-AP after stroke and TBI. The beneficial role of Cav-1 in stroke led us to hypothesize that intraperitoneal injection of Cav-AP will inhibit eNOS activation and possibly JNK in endothelial cells thereby facilitating NVU recovery, reducing oedema and decreasing neuronal death to significantly improve behavioural outcomes. We will test our hypothesis in rodent models of transient middle cerebral artery occlusion for stroke and controlled cortical impact for TBI, by comparing the molecular mechanisms in the pathological models as described below. Addressing this in two different models and labs will provide a unique opportunity to determine whether both pathologies share similar molecular mechanisms in NVU repair, combining molecular and behavioural evaluations. Aim 1: Determine the protective effects of endogenous Cav-1 and injection of cav-AP on the NVU and behavioural outcome after stroke and TBI. We will examine the effects of absence of Cav-1 (using knockout mice for Cav-1, Cav1-/-) and “extra”-Cav-1 (cav-AP injection), compared to controls after stroke and TBI at 4h, 1d, 3d and 7d. We will assess multiple behavioral endpoints, oedema formation (T2 & diffusion weighted imaging), BBB permeability (gadolinium leakage), CBF (perfusion weighted imaging), molecular changes in BBB structure, and brain histology. Changes in JNK and eNOS will be evaluated by Western blots, immunohistochemistry and enzymatic assays on brain tissue and isolated blood vessels. We hypothesize that increasing the availability of Cav-1 CSD will inhibit JNK and eNOS pathways, decrease BBB disruption, reduce oedema formation, improve CBF, and prevent smooth muscle transformation. These improvements will result in better overall behavioral outcomes with less neuronal cell death and astrogliosis. We expect the opposite effects in Cav-/- mice. Aim 2: Determine the effects of total JNK inhibition on the NVU and behavioural outcomes after stroke and TBI. We will determine if JNK is activated in endothelial cells after stroke and TBI. We will examine the effects of total inhibition of the JNK pathway (with the peptide DJNKI1) on the outcomes and molecular endpoints mentioned in aim 1 after TBI and stroke at 4hours, 1d, 3d and 7d. We hypothesize that JNK inhibition will decrease eNOS activation and NO production, and consequently preserve BBB function, CBF regulation and will improve behavioural outcomes mimicking the effects of cav-AP administration. Aim 3: Determine the effects of eNOS inhibition after stroke and TBI on the NVU and behavioural outcomes. We will examine the effects of eNOS inhibition (with L-NIO) and compare it to inhibition of all NOS isoforms (with L-NAME) on the outcomes and molecular endpoints from aim 1 after TBI and stroke at 4h, 1d, 3d and 7d. We hypothesize that inhibition of eNOS will be sufficient to decrease NO production, preserve BBB function, CBF-regulation, smooth muscle phenotype and will improve behavioral outcome mimicking the effects of the cav-AP administration. The experiments will advance our knowledge of TBI and stroke pathophysiology and the complex interactions between the vasculature and brain cells. Importantly, it will bring information on how ischemic and traumatic pathological mechanisms merge. We expect to demonstrate that cav-AP has significant potential as a new treatment for TBI and stroke at early and long-term time points. The future goal of this program is to develop cav-AP as a therapy for both stroke and TBI and possibly other brain diseases that involve NVU dysfunction.
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