PhD Position in EU Doctoral Network "PANDORA"

The position focuses on "Evaluating how complement dysregulation influences mononuclear phagocyte accumulation in AMD" within the MSCA Doctoral Network PANDORA (Discovering Pathomechanisms and Novel Drug Optimization for AMD).

Subretinal mononuclear phagocytes (MPs) build up in the photoreceptor cell layer, a zone normally kept free of immune cells by the immunosuppressive retinal pigment epithelium (RPE). This build-up is a key driver of age-related macular degeneration (AMD). MPs include microglia and monocyte-derived inflammatory macrophages (MoMφ). Our team has shown that activated MPs evade RPE-mediated clearance. We have also shown that the AMD-linked CFH 402H variant impairs the removal of subretinal MPs independently of its role in the complement system. How complement dysregulation contributes to immune cell accumulation in the subretinal space in AMD remains poorly understood.

The PhD student will first map where complement cascade components are found in the human retina. Using multiplexed immunohistochemistry on post-mortem retinal sections from AMD donors and age-matched controls, the student will localise components of the classical, lectin and alternative pathways, their activation products, regulators (CFH and Factor H-related proteins) and receptors. These components will be mapped relative to subretinal MPs, the RPE, photoreceptors and drusen.

The student will then study how the Chromosome 1 (Chr1) AMD risk haplotype affects RPE, microglia and MoMφ and their interactions. They will use control and Chr1-risk iPSC-derived cells in a well-defined co-culture system developed in our laboratory. The student will also study the role of plasma-derived Factor H-related proteins (FHR1-5) using depleted human plasma and purified complement factors.

Using single-cell and bulk RNA sequencing and proteomics, the student will analyse how complement dysregulation affects:

• microglia and MoMφ polarisation
• the interaction of these cells with the immunosuppressive RPE
• key inflammatory pathways and immune functions in the subretinal microenvironment, in health and in AMD

Finally, the student will test whether complement inhibitors (anti-C5, anti-C3) can restore immune balance.

The project is supervised by Dr. Florian Sennlaub (Institut de la Vision, Paris) It is carried out in close collaboration with other PANDORA doctoral candidates.

Techniques and Training Include:

• Multiplexed immunohistochemistry on human donor retinal sections (AMD and age-matched controls), whole-slide/confocal imaging and quantitative image analysis
• Induced pluripotent stem cell (iPSC)-derived RPE, microglia and macrophage models, and immune cell/RPE co-cultures
• Primary human monocyte isolation and differentiation, and work with human plasma and purified complement factors
• Single-cell and bulk transcriptomics, and proteomics
• Flow cytometry, qPCR, western blot, ELISA/multiplex cytokine assays
• Functional immune assays (phagocytosis, migration, survival/clearance)

Founded by Professor José-Alain Sahel, the Institut de la Vision is an international research centre dedicated entirely to research into eye and vision diseases. It brings together researchers, doctors, patients and industry on the same site to discover innovative treatments for eye diseases and improve the quality of life of visually impaired people.

It is being built on a site that brings together l’Hôpital national de la vision des 15-20 and its Clinical Investigation Centre (CIC), as well as the Centre for Rare Retinal Diseases. Designed as a place where people can come together and exchange ideas, the Institut de la Vision enables ideas to be shared, new questions to emerge and the transfer of research findings to patient care to be accelerated. Its innovative organisation, based around hospital patients, enables new therapeutic or technological solutions to be discovered, tested and developed in order to prevent eye diseases or limit their effects.

More than 300 researchers are working in the 5 research departments of the Institut de la Vision: developmental biology of the visual system, genetics, visual information processing, pathophysiology and therapeutics, photonics.

All the Institut de la Vision's activities and projects are coordinated by its Foundation (Foundation Institut de la vision), in conjunction with its three supervisory bodies: Sorbonne University, Inserm and the CNRS.

Education Level: Master's Degree or equivalent in life sciences, biology, immunology, neurobiology or biomedical sciences

Essential Skills/Qualifications:

• Solid knowledge of cellular and molecular biology and/or immunology
• Excellent written and oral English proficiency
• Strong motivation for research on retinal degeneration and neuroinflammation
• Ability to work both in a team and independently

Preferred Qualifications:

• Hands-on experience in cell culture (ideally primary immune cells or iPSC-derived cells) and flow cytometry
• Experience with immunohistochemistry/immunofluorescence and image analysis
• Background in innate immunity, macrophage/microglia biology and the complement system
• Interest in, or basic experience with, omics data analysis

Language: Excellent English (French not required)

Applicants must meet these requirements:

• They must not have resided or carried out their main activity (work, studies, etc.) in France for more than 12 months in the 36 months before the recruitment date. Compulsory national service and time spent in refugee status procedures are excluded.
• They must not already hold a doctoral degree.
• They can be of any nationality.