Marie Curie (MSCA) PhD fellowship in NAD biology in brain disease (ESR3)

Imagine Institute, Paris, France

Université Paris Cité

Offer Description

We have a vacancy for a doctoral researcher funded through the EU-Horizon NADIS Marie Skłodowska-Curie Network commencing April 1, 2023, or after agreement. The project will be mainly developed at the Laboratory of Mechanisms and Therapy of Genetic Brain Disease (Imagine Institute, Paris, France). The candidate will become part of a larger network of researchers across top universities in Europe.

Principal supervisor is Michela Deleidi, Imagine Institute, Paris (France)

email michela.deleidi@institutimagine.org

Project description

Project title: “Targeting NAD+ metabolism to improve proteostasis and immune homeostasis in neurodegenerative diseases”.

This project aims to generate a deep understanding on how NAD+ metabolism is linked to neurodegenerative disease, and the application of NAD+ repletion strategies to counteract age-associated brain disorders. Loss of NAD is emerging as a central feature in aging and age-associated disease. Importantly, NAD levels can be increased by ingestion of molecular precursors such as nicotinamide riboside and nicotinamide mononucleotide. Recently, we have shown that 3D systems, as compared with 2D systems, provide a more relevant disease model that is advantageous in investigating the link between cellular proteostasis and disease. Importantly, we have demonstrated that stem cell-derived organoids represent a relevant model to test the role of NAD+ targeting compounds. Here, we will evaluate the effect of NAD+ precursors on protein aggregation and spreading as well as inflammatory pathways in these newly developed organoid models. Long-term culture organoids will be supplemented with NAD+ enhancers and compared at the cellular, biochemical, and transcriptomic level. To determine metabolic changes upon supplementation with NAD+ enhancers, metabolomics, and lipidomics analyses will be performed in a collaboration with AUMC.

Your main tasks and responsibilities in this project will be:

-To perform cell culture experiments in 3D cultured human intestinal and brain organoids

-To apply several techniques to determine changes in NAD+ metabolism in genetic brain disease models

-To participate in experimental design

-To actively communicate and disseminate the results of the research

The NADIS network

The main goal of the NADIS consortium is to train the next generation of metabolic researchers, providing them with in-depth knowledge and cross-disciplinary expertise to combat disease. The research projects will specifically focus on the metabolism of NAD+, a central redox cofactor and enzymatic substrate that plays an essential role in virtually all major cellular functions. The limited knowledge on the interplay between NAD+ and the cellular processes in which it is involved, especially those that lead to disease, requires novel experimental and analytical tools combined with a strong interaction between scientists and clinical staff coming from different disciplines. We aim to fill these gaps by training ten highly skilled ESRs. To do this, we bring together our expertise in molecular and cellular biology, bioinformatics, and Artificial Intelligence (AI), omics, drug development and nutritional/clinical applications. Our non-academic beneficiaries are focused on the development of nutrition products, medical foods, and drug development for new therapies. We will also provide ESRs with transferable and networking skills, and first-hand experience of industrial applications, enabling them to become future leading scientists at the forefront of metabolic research and, specifically, NAD+ research in Europe.

Our group and research

Our research aims at studying how discrete genetic factors contribute to the development of genetic neurological disorders. To this end, we develop models with human pluripotent stem cells and long-term cultures of organoids combined with single cell-omics to identify the role of disease related genetic variants and validate targets with diagnostic and therapeutic potential.

Why joining Institut Imagine?

Institut Imagine, on the Necker Sick Children Hospital campus in Paris, is an interdisciplinary biomedical research centre, providing excellent core facilities for genomics, cell imaging, and bioinformatics together with creating animal models of human disease (mice, Zebrafish, and Drosophila). Additionally, Imagine strongly emphasizes translational aspects and innovative therapeutic options, including gene therapies. Imagine, supported by a private Foundation, is affiliated with Université Paris Cité, INSERM (French national institute for medical research) and the greater Paris Public Hospitals Group (Assistance Publique-Hôpitaux de Paris).As a research and healthcare Institute, Imagine focuses on a wide variety of genetic diseases, studying all aspects of from basic research to translational medicine with an ultimate aim of developing new approaches to therapy including gene therapy and gene editing. The Institute includes over 600 staff members in 28 laboratories organized in integrated care and research programs addressing genetics, immunology and infectious diseases, haematology, nephrology, developmental defects, neurosciences and bioinformatics. All groups address these issues with wet lab, computational approaches, or both. Their projects are deeply entangled with clinical units and referral centres for rare diseases affiliated to the institute. Imagine Institute of genetic diseases offers a stimulating and ideal environment to train and develop the career of young researchers, PhD students and post-docs.