DESCRIPTION :
The AIstroSight team develops innovative computational methods for neuropharmacology and the discovery of new drug candidates to treat brain diseases.
More details are available on our website: https://team.inria.fr/aistrosight/
Mission confiée
Background and rationale
Alzheimer's disease (AD), the most common cause of dementia, is a multifaceted neurodegenerative disease. Research has identified numerous cell types and pathological mechanisms involved in disease development. Yet, targets that would significantly hinder the progression of AD in patients remain to be identified. Historically, studies have focused on tau tangles and ß-amyloid (Aß) deposition, which were observed in postmortem AD brains^1. Recently, blood vessel dysfunction has been reported as a feature of early stages of AD^2. Understanding the cell-cell interactions that maintain brain vasculature and how they are altered in AD is thus crucial to address the effects of these vascular changes on disease progression.
The blood-brain barrier (BBB) is comprised of multiple cells including astrocytes^3, that are uniquely positioned to mediate interactions between neurons and blood vessels via a specialized compartment called the astrocyte endfoot. In addition to maintaining BBB integrity, astrocyte endfeet regulate the blood flow (neurovascular coupling), nutrient uptake, and waste clearance^4. While astrocyte and vascular dysfunction are early features of AD, how these alterations relate to each other and contribute to disease progression is not known. The identification of these mechanisms could thus shed light on pathways that could be targeted to preserve brain health in AD.
Goal of the internship
The goal of this internship is to integrate structural and proteomics signatures of astrocyte endfeet at different stages of AD to evaluate the functional consequences of these alterations. This in silico work will focus on neurovascular coupling which is in part mediated by astrocytes^5,6 and is altered in AD^7. An initial model of neurovascular coupling at endfeet in control mice has been implemented in the lab (Dupeuble et al., in prep). The first goal of this internship is to spatialize this model to allow simulations in complex realistic geometries, ideally via variational formula for the reaction-diffusion equations. The second objective is to leverage endfoot proteomics data measured in vivo by the Díaz Castro lab (University of Edinburgh, Scotland)^8 to investigate the impact of altered protein expression levels observed at different stages of AD progression (unpublished) on NVC.
Simultaneously, simulations will consider structural alterations of endfeet in AD (unpublished) measured using the FIB-SEM volume EM method of the Murai Lab (McGill University, Canada)^9 to infer mechanistic links between endfoot structure and altered NVC in AD. The model will be developed using partial differential equations following the mass action law and Michaelis-Menten kinetics. In silico experiments will be performed using FEniCs software to allow simulations in volume EM 3D cell reconstructions. The model's output corresponds to radius variations of blood vessels following neuronal stimulation. The model will be validated with experimental data from the literature (e.g. from Institoris et al.^10 for control mice).
This computational work will be instrumental to propose functional consequences of structural and molecular endfoot changes in AD reported by our collaborators, and will set the foundation for future work to identify pathways that could be targeted to prevent AD progression.
References
1. Serrano-Pozo, A., Frosch, M. P., Masliah, E. & Hyman, B. T. Neuropathological Alterations in Alzheimer Disease. Cold Spring Harb Perspect Med 1, a006189 (2011).
2. Iturria-Medina, Y., Sotero, R. C., Toussaint, P. J., Mateos-Pérez, J. M. & Evans, A. C. Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis. Nat Commun 7, 11934 (2016).
3. Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R. & Zlokovic, B. V. Blood-Brain Barrier: From Physiology to Disease and Back. Physiological Reviews 99, 21-78 (2019).
4. Díaz-Castro, B., Robel, S. & Mishra, A. Astrocyte Endfeet in Brain Function and Pathology: Open Questions. Annual Review of Neuroscience 46, 101-121 (2023).
5. Petzold, G. C. & Murthy, V. N. Role of Astrocytes in Neurovascular Coupling. Neuron 71, 782-797 (2011).
6. Attwell, D. et al. Glial and neuronal control of brain blood flow. Nature 468, 232-243 (2010).
7. Kisler, K., Nelson, A. R., Montagne, A. & Zlokovic, B. V. Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci 18, 419-434 (2017).
8. Hill, S. A. et al. Molecular profiling of brain endothelial cell to astrocyte endfoot communication in mouse and human. Nat Commun 16, 9750 (2025).
9. Salmon, C. K. et al. Organizing principles of astrocytic nanoarchitecture in the mouse cerebral cortex. Current Biology 0, (2023).
10. Institoris, A. et al. Astrocytes amplify neurovascular coupling to sustained activation of neocortex in awake mice. Nat Commun 13, 7872 (2022).
11. Francis, E. A. et al. Spatial modeling algorithms for reactions and transport in biological cells. Nat Comput Sci 1-14 (2024) doi:10.1038/s43588-024-00745-x.
12. De Pittà, M., Ben-Jacob, E. & Berry, H. G Protein-Coupled Receptor-Mediated Calcium Signaling in Astrocytes. in Computational Glioscience (eds De Pittà, M. & Berry, H.) 115-150 (Springer International Publishing, Cham, 2019). doi:10.1007/978-3-030-00817-8_5
Principales activités
In this context, the intern is expected to:
* conduct a literature review on finite element algorithms suited to simulations in complex geometries (e.g. SMART^11) and astrocyte models, in particular spatial models
* develop a PDE model of calcium signaling based on the G-ChI model of astrocyte calcium signaling^12
* calibrate the model with calcium recordings from the literature
* extend the model to neurovascular coupling, based on a model developed in the lab (Dupeuble et al., in prep.)
* adapt the model to protein expression changes reported during AD progression
* design and conduct in silico experiments to study NVC at endfeet in healthy and AD conditions
During this internship, the intern will participate to a joint meeting in Edinburgh with the collaborating teams.
Code d'emploi : Musicien (h/f)
Domaine professionnel actuel : Musiciens, Chanteurs et Danseurs
Niveau de formation : Bac+3
Temps partiel / Temps plein : Plein temps
Type de contrat : Stage/Jeune diplômé
Compétences : ARM Architecture, Simulation Informatique, Données Expérimentales, Python (Langage de Programmation), Tests Basés sur les Données, Anglais, Français, Sens de l'Organisation, Algorithmes, Maladie d'Alzheimer, Physiologie, Mathématiques Appliquées, Biologie, Neurodégénération, Découverte de Médicament, Expérimentation, Méthodes par Éléments Finis, Gestion des Pathologies, Modélisation Mathématique, Biologie Moléculaire et Cellulaire, Neurosciences, Équation Différentielle Partielle, Référencement Web (SEM), Simulations, Etudes et Statistiques, Science des Données, Protéines, Informations Compartimentées Sensibles, Expression des Protéines, Maladies Démentielles, Signalisation
Courriel :
audrey.denizot@inria.fr
Téléphone :
0139635511
Type d'annonceur : Employeur direct
