eIF5A hypusination as a pharmacological target to improve ischemia-reperfusion during liver transplantation

16 Apr 2024
Job Information

Organisation/Company

Université de Poitiers

Research Field

Biological sciences » Biology
Medical sciences » Health sciences

Researcher Profile

First Stage Researcher (R1)

Country

France

Application Deadline

15 May 2024 - 18:00 (Europe/Paris)

Type of Contract

Temporary

Job Status

Full-time

Offer Starting Date

1 Oct 2024

Is the job funded through the EU Research Framework Programme?

Not funded by an EU programme

Is the Job related to staff position within a Research Infrastructure?

No

Offer Description

Abstract: To face the constant need in organ transplantation (Tx) and the lack of available grafts, it becomes critical to improve graft tolerance to the transplantation stresses happening during this procedure and therefore, improve Tx outcome on short and long term. Ischemia-reperfusion (IR) and its associated injuries (IRI) occurring during the Tx are one of the key aspects and among the most studied to understand and improve the normal function of the graft. In this context, we propose to use an innovative approach, notably using multiphoton microscopy, to 1/ describe hepatic ischemia-reperfusion at the cellular, tissular and functional level longitudinally, 2/ study the potential protector effects of eIF5A hypusination inhibition, a pharmacological target previously identified, 3/ characterize this protection to finally 4/ identify new pharmacological targets to be used in translational models and ultimately in clinic.

Context and main question: To this day, transplantation (Tx) is the last considered treatment that can be used to cure chronic pathologies (nephropathy, cancer, cirrhosis...), that would, if untreated, lead to a major organ failure and death. Beside the complex procedure, the main limitation is the availability of usable graft: in France alone, in 2024, almost 22.000 patients are on a waiting list for a transplantation (particularly renal and hepatic). Recently, efforts have been made to increase available graft, by considering ones defined as “marginal”, and generally by improving graft resuming its normal function post transplantation. This entails a better tolerance toward IR injuries (IRI) happening during Tx. In this context, we are proposing to develop new models to particularly study IR tolerance in the liver and to evidence pharmacological targets that could be use in a clinical context.

Project description: We previously demonstrated that in renal Tx, inhibition of eIF5A hypusination increased IR tolerance at the cell, tissue and functional level. Hypusination is a post-translational modification unique to eIF5A, a translation factor, and this modification is critical to its function. The protection led to a clear and deep cell reprogramming (metabolic, ER and oxidative stress tolerance...) whose exact molecular targets remained to be characterized.

This study’s goal is to evidence that this IR tolerance can be transposed to the liver, notably by the preservation of the biliary ducts, particularly sensitive to IRI and a key structure for a favorable outcome of the Tx. This study also aims to understand the molecular determinants of IR tolerance and identify new pharmacological targets that could be used in a (pre)clinical model.

Experimental approach: To study the tolerance of liver to IRI, we will use a multi-level approach on the most relevant models, for most part already established in the lab.

• Cell models with various degrees of complexity to perform pharmacological and mechanistic studies: hepatocytes culture, cholangiocytes-hepatocytes co-culture, 3D models (liver organoids...).
• Functional murine models to mimic kinetics and problematics of the hepatic Tx: Liver IR developed and used in the lab.

Beside classical cell biology and biochemistry techniques needed to address those questions, this study will deeply use light microscopy and particularly multiphoton microscopy. This will allow us to study large samples by tissue clearing, to follow dynamically and longitudinally metabolic processes (NADH, FADH fluctuations) as well as cellular and extracellular nature and organization (Collagen-I SHG, molecule ID via FLIM…).

Requirements

Research Field

Biological sciences

Education Level

Master Degree or equivalent

Skills/Qualifications

The ideal candidate must have obtained a master 2 in biology or biotechnologies and have solid knowledge of cell biology / biochemistry /physiology and if possible, in light microscopy (epifluorescence, confocal, multiphoton…) or have a strong interest to learn those approaches. He or she will show motivation, curiosity, pro-activity and autonomy. He or she will join a stimulating, collaborating and friendly work environment. An animal work is part of the project and therefore the candidate will agree to work with such models. Animal experimentation diploma is needed but can be acquired in the lab. Very good spoken and written English is required to communicate in the lab and particularly with the group international network of collaborators.

Specific Requirements

To apply: send a resume + motivation letter + Master (1 & 2) grades and ranking + contact infos for at least 2 referents/mentors

Languages

ENGLISH

Level

Good

Research Field

Biological sciences » Biology

Additional Information
Work Location(s)

Number of offers available

1

Company/Institute

IRMETIST - U1313

Country

France

City

Poitiers

Geofield

Where to apply

E-mail

[email protected]

Contact

City

Poitiers

Website

https://irmetist.labo.univ-poitiers.fr/

E-Mail

[email protected]

STATUS: EXPIRED