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Intitulé du sujet: Regulation and role of NOX1 in colon organoids of healthy individuals and patients with inflammatory Bowel disease in response to the microbiota and its derived metabolites.

Sujet

Codirection:

Nombre de mois: 48 mois

Ecole Doctorale: ED 562 - Bio Sorbonne Paris Cité

Unité de recherche et équipe:

INSERM  U1149-EMR8252 Centre de Recherche sur l’Inflammation.

Team  "Phagocytes and NADPH‐Oxidases in Iinflammation", Current team leader: Jamel El-BENNA (until end of 2024)

Starting January 1, 2025, team leader: Pham My-Chan DANG (approved by INSERM and HCERES wave D)

Coordonnées de l’équipe:

Equipe "Phagocytes et NADPH‐Oxydases dans l’inflammation"

INSERM U1149 - ERL8252, 

Centre de Recherche sur l'Inflammation

Faculté de Médecine Xavier Bichat

16 rue Henri-Huchard 75018, Paris, FRANCE

Secteur: Sciences de la vie / Life Sciences

Langue attendue: Anglais

Niveau de langue attendu: B2

Description

Description du sujet:

NADPH oxidases (NOX) are enzymes which are exclusively dedicated to the generation of reactive oxygen species (ROS) [1].  When properly regulated, NOX-derived ROS are essential for several physiological processes. Thus, ROS production by the phagocyte NADPH oxidase (NOX2) is required for host defence against pathogens while ROS generation by NADPH oxidase of epithelial cells (NOX1) has been involved in intracellular signaling. However, as ROS are inherently cytotoxic molecules, inappropriate and excessive ROS production by the NOX enzymes can induce severe tissue injury contributing to a wide range of chronic inflammatory diseases. Consequently, ROS production must be tightly regulated and understanding the mechanisms involved in the regulation of NOXs activity and their functions is essential to identify novel therapeutic targets and novel biological markers in inflammatory diseases. NOX1 which is composed of several membrane (Nox1, p22PHOX) and cytosolic (NOXO1, NOXA1, Rac1) subunits,  is expressed predominantly in colon epithelial cells and as such is permanently exposed to the microbiota and its derived metabolites [2-4], however its regulation by the microbiota and its derived metabolites remains poorly understood in physiological and pathophysiological situations.

In this context, the primary objectives of this project are to investigate the regulation and function of NOX1 in colon organoids derived from healthy individuals and patients with Inflammatory Bowel Disease (IBD) in response to the microbiota and its metabolites, aiming to elucidate its role in both physiological and pathological conditions. Specifically we will:

1. Compare NOX1 in Healthy vs. IBD Organoids: We will evaluate whether NOX1 expression, phosphorylation, and activity are altered in IBD patients compared to healthy individuals. This analysis will be conducted under basal conditions and following stimulation with microbiota or microbiota-derived metabolites.

2. Identify NOX1 Downstream Effectors: We will characterize the downstream signaling pathways and effectors regulated by NOX1 in both healthy and diseased organoids to understand its impact in immune and inflammatory response.

3. Analyze epithelial Cell-Neutrophil Crosstalk: We will study the interactions between epithelial cells and neutrophils using co-culture models of colon organoids (healthy or IBD-derived) and neutrophils. This will provide insights into how NOX1 influences immune-epithelial communication in health and disease.

This project will advance understanding of NOX1's role in intestinal homeostasis and its dysregulation in IBD. By investigating its regulation, downstream effectors, and contribution to epithelial-immune crosstalk, the findings could pave the way for novel therapeutic strategies targeting NOX1 or its associated pathways in IBD.

 

Compétences requises:

1. Fluent English

2. Having completed an internship of at least six months in a research laboratory.

3. Good background in Immunology, Cellular biology and Biochemistry

Références bibliographiques:

  1. El-Benna J, Hurtado-Nedelec M, Marzaioli V, Marie JC, Gougerot-Pocidalo MA, Dang PM. Priming of the neutrophil respiratory burst: role in host defense and inflammation. Immunol Rev. 2016 Sep;273(1):180-93. doi: 10.1111/imr.12447. PMID: 27558335.
  2. Dang PM, Rolas L, El-Benna J. The Dual Role of Reactive Oxygen Species-Generating Nicotinamide Adenine Dinucleotide Phosphate Oxidases in Gastrointestinal Inflammation and Therapeutic Perspectives. Antioxid Redox Signal. 2020 Aug 10;33(5):354-373. doi: 10.1089/ars.2020.8018.
  3. Makhezer N, Ben Khemis M, Liu D, Khichane Y, Marzaioli V, Tlili A, Mojallali M, Pintard C, Letteron P, Hurtado-Nedelec M, El-Benna J, Marie JC, Sannier A, Pelletier AL, Dang PM. NOX1-derived ROS drive the expression of Lipocalin-2 in colonic epithelial cells in inflammatory conditions. Mucosal Immunol. 2019 Jan;12(1):117-131.
  4. Liu D, Marie JC, Pelletier AL, Song Z, Ben-Khemis M, Boudiaf K, Pintard C, Leger T, Terrier S, Chevreux G, El-Benna J, Dang PM. Protein Kinase CK2 acts as a molecular brake to control NADPH oxidase 1 activation and colon inflammation. Cell Mol Gastroenterol Hepatol. 2022, 13(4):1073-1093.