PROJECT 7

The role of retinal Mononuclear Phagocytes and Macroglia cells in retinal ischemia

Why?
Glaucoma is characterized by retinal ischemia, central BRB alteration ang retinal ganglion cell (RGC) loss. Hyperlipidemia is associated with elevated ocular intraocular pressure (IOP) leading to glaucoma. Retinal ischemia such as observed in glaucoma or during ischemic retinopathies is characterized by activation of local microglial cells (MC) and macroglial cells (retinal Muller Glial (RMG) cells) which collectively participate in neuronal cell death. A comprehensive view of MC and RMG interplays in a complex glaucoma associated stress (hypoxia, dyslipidemia and glucose deprivation, mitochondrial dysfunction, inflammation) is needed to propose innovative treatment for patient with glaucoma.

How?
The project will used recently characterized iPS derived RMG and differentiated MC as well as brain organoids and innovative models of retinal ischemia developed in host and the secondment laboratories. iPS derived-RMG and -MC cells will be co-cultured and stimulated with the above-mentioned glaucoma-associated stress. MC and MG activation and MC/MG interaction will be analyzed by state-of-the-art cell phenotyping (luminex analysis, FACS, RNA sequencing, Seahorse technology, metabolomics, IncuCyte, multi-electrode array) and their participation to RGC death/survival will be evaluated on organoids or flatmounted retina. We will focus on the interaction between neurons and glia cells and investigate how modulation of neuroinflammatory pathways affect neuronal function and survival. Candidate therapeutic compounds, or compounds selected from libraries using a high throughput facility will be evaluated on MC, MG or MC/MG activation and RGC cell death.

What can you expect?
The candidate will benefit from internationally recognized expertise in the field of induced pluripotent stem cell derived MC and RMG cell culture1,3. The host laboratories have strong expertise in retinal inflammation, cell death mechanisms and deep retinal phenotyping (FACS, transcriptomic and single cell transcriptomic)1-5. The candidate will be trained to use all these techniques to tackle glial dependent RGC cell death.

Where?
The research project is a joint-doctorate between the Institut de la Vision (FR) (host) and the Faculty of Science and Engineering of the University of Groningen (NL). The candidate’s host, the Vision Institute (Sorbonne-Université) is one of the largest European center for integrated vision research. Located in Paris at the heart of the National Opthalmology Hospital, it brings together fundamental, clinical and industrial research on the same site in order to accelerate the transition between basic and applied research. Institut de la vision combines all the sate of art technological and eye specialized (surgery, imaging, vision evaluation) facilities. Here, the candidate part of Xavier Guillonneau’s lab, that focuses on the involvement of inflammatory mechanisms in retinal vascular diseases (diabetic retinopathy and retinopathy of prematurity) and in neurodegenerative processes associated with age related macular degeneration. At the seconded institute, the Faculty of Science and Engineering (University of Groningen), the candidate will be supervised by Amalia Dolga, professor in Regenerative Neuropharmacology with an expertise in neurodegeneration, mitochondrial function, inflammation, potassium channels.

Who are we looking for?
Highly-motivated candidates with ample experience with cell culture (ideally stem cell culture) and a strong interest in mechanisms of cell death and inflammation. The candidate is expected to be self-motivated, curious, proactive and have strong communicational skills. As the student will be appointed on a double degree program, part of the project will be performed in France and another part in the Netherlands.

References

  • Couturier, A., Blot, G., Vignaud, L., Nanteau, C., Slembrouck-Brec, A., Fradot, V., Acar, N., Sahel, J.A., Tadayoni, R., Thuret, G., Sennlaub, F., Roger, J.E., Goureau, O., Guillonneau*, X., and Reichman*, S.,Reproducing diabetic retinopathy features using newly developed human induced-pluripotent stem cell-derived retinal Muller glial cells, Glia (2021). 10.1002/glia.23983.
  • Majerníková N, den Dunnen WFA, Dolga AM. The Potential of Ferroptosis-Targeting Therapies for Alzheimer’s Disease: From Mechanism to Transcriptomic Analysis. Front Aging Neurosci. 2021 Dec 20;13:745046.
  • Sabogal-Guáqueta AM, Marmolejo-Garza A, de Pádua VP, Eggen B, Boddeke E, Dolga AM. Microglia alterations in neurodegenerative diseases and their modeling with human induced pluripotent stem cell and other platforms. Prog Neurobiol. 2020 Jul;190:101805.
  • Neitemeier S, Jelinek A, Laino V, Hoffmann L, Eisenbach I, Eying R, Ganjam GK, Dolga AM, Oppermann S, Culmsee C. BID links ferroptosis to mitochondrial cell death pathways. Redox Biol. 2017 Aug;12:558-570.
  • Guillonneau, X., Eandi, C.M., Paques, M., Sahel, J.A., Sapieha, P., and Sennlaub, F.,On phagocytes and macular degeneration, Progress in Retinal and Eye Research (2017). 10.1016/j.preteyeres.2017.06.002.