PhD Position is open in the laboratory of Imaging and Brain within Inserm research Unit U1253 in Tours, France (www.u930.tours.inserm.fr).
Neurophysiological consequences of
acoustically-mediated blood-brain barrier opening
Context – Due to an aging population, the treatment of neurodegenerative diseases such as Alzheimer’s disease is a major public health issue. Nowadays, European Union has more than 180 million people suffering from neurodegenerative diseases. With more than 500,000 new cases diagnosed each year, the epidemiological peak is ahead of us. Despite the development of therapeutic molecules targeting the proteins involved in these diseases, the marketing of these molecules is limited by the lack of specific delivery of these molecules in the brain. Moreover, the inability of these molecules to cross the blood-brain barrier (BBB) is another major limitation. Current methods of intracerebral delivery of therapeutic molecules induce disturbance of the BBB throughout the volume of perfused tissue and cannot be used for targeted delivery. In this context, the notion of active delivery is of great interest because it implies both effective formulation and better targeting. The specific delivery of drugs to the brain continues to be a major challenge for the treatment of neurodegenerative diseases.
Ultrasound contrast agents, consisting of gas microbubbles, are used in diagnosis during contrastenhanced ultrasound imaging. In recent years, new promising methods for the local delivery of anticancer drugs or nucleic acids based on the use of these microbubbles have been proposed. This possibility, in combination with ultrasound (i.e., sonoporation), provides unprecedented alternatives for effective and non-invasive therapeutic action. The term “sonoporation” denotes a process by which the activation of microbubbles by ultrasound near the BBB transiently increases its permeability and thus allows the extravasation and penetration of therapeutic molecules into the cerebral parenchyma. By virtue of this extravasation, the bioavailability of these molecules in the cerebral parenchyma is increased, thus improving the therapeutic index.
Issue – While many studies describe the opening of the BBB and the improvement in the biodistribution of drugs in the brain using sonoporation, the safety of this procedure in the short, medium and long term is little known.
Objective – In this context, we propose to study the physiological consequences of sonoporationinduced BBB opening after sonoporation on neuroinflammation and neurotransmission processes.
Two main hypotheses will be investigated:
- 1 – Does the acoustically-mediated BBB permeabilization induce neuroinflammation?
- 2 – Does this procedure disrupt the neurotransmission?
Methodology – To achieve our goals, we will use an in-vitro BBB model and a physiological murine model. Neurogenomic and neurometabolomics approaches will allow us to study the impacts of the acoustically-mediated BBB opening on the expression of genes and the production of metabolites involved in neuroinflammation and neurotransmission processes. Finally, the impact of this procedure on the organization of the brain tissue will be undertaken by optical and electronic microscopy.
References – Madji Hounoum B, Mavel S, Coque E, Patin F, Vourc’h P, Marouillat S, NadalDesbarats L, et al., (2017). Wildtype motoneurons, ALS-Linked SOD1 mutation and glutamate profoundly modify astrocyte metabolism and lactate shuttling. Glia., 592-605; Diémé B, Lefèvre A, Nadal-Desbarats L, et al., (2017). Workflow methodology for rat brain metabolome exploration using NMR, LC-MS and GC-MS analytical platforms. J Pharm Biomed Anal., 142:270-278; Escoffre JM, Derieppe M et al., (2017) Microbubble-assisted ultrasound-induced transient phosphatidylserine translocation. Ultrasound Med. Biol., 43:838-851; Escoffre JM et al., (2013) Irinotecan delivery by microbubble-assisted ultrasound: In-vitro validation and a pilot preclinical study. Mol. Pharm., 10:266775.
MSc Degree (Master 2)
- Mandatory skills:
- Skills in Neurophysiology, Cell biology and Biochemistry;
- Skills in Statistics (R, Prism); o Synthesis and editorial skills are required;
- Fluency in English;
- Contribution to collective life of the team as well as the research (Seminars, Méridiennes) and to outreaching activities (Science Festival, Brain Awareness Week). Optional skills:
- Skills in Acoustics; o Skills in Animal experimentation / Certificate for Animal experimentation.
PhD Grant – PhD Grant from the French Ministry of High Education, Research and Innovation.
- Curriculum Vitae;
- Cover letter;
- Sc. Transcripts;
- Coordinates Two referees (First name, Last name, Phone number, Email);
Send to Dr. Lydie Nadal-Desbarats (firstname.lastname@example.org) and Dr. Jean-Michel Escoffre (email@example.com).