Exploring a novel therapeutic approach to mitigate motor impairments resulting from brain lesions in children with cerebral palsy

State of the Art

Cerebral palsy (CP) encompasses a group of motor disorders affecting movement, posture, and muscle tone. It results from brain damage occurring during development, caused by factors such as maternal-fetal infections, neuroinflammation, placental insufficiency, or perinatal complications. Although CP affects 1 to 2 newborns per 1000 live births, its pathophysiological mechanisms are still poorly understood, and no curative treatment is currently available. Therefore, it is essential to identify cellular markers of these dysfunctions in order to translate them into therapeutic advances.

The endoplasmic reticulum (ER) is a key player in the cellular stress response and the maintenance of cellular homeostasis. When exposed to stress, it triggers an adaptive response, the Unfolded Protein Response (UPR), aimed at restoring its balance. However, prolonged or inappropriate ER stress impairs brain plasticity and may contribute to the motor deficits observed in CP. Notably, markers of ER stress have been identified in the blood and brain of rats with neonatal hypoxic-ischemic brain lesions (Chavez-Valdez IJMS 2016). Moreover, experimental ER stress inhibitors have shown beneficial effects on motor and cognitive phenotypes in animals (Wu Front Behav Neurosci 2021), suggesting that ER stress could be a potential therapeutic target for CP.

Hypothesis

We hypothesize that early modulation of ER stress and the UPR could limit brain damage, improve motor abilities in children with CP, and thereby reduce the severity of their disability.

Objectives and Methodology

In collaboration with S. Sizonenko and E. Sanches (Geneva), we analyzed ER stress in two reference rat models that simulate the most common causes of CP in children: the HI model (hypoxic-ischemic brain lesions at day 3) and the CP model (brain lesions caused by maternal exposure to a bacterial endotoxin, perinatal anoxia, and sensorimotor restriction for 21 days post-lesion). Our analyses show an increase in ER stress and UPR markers in the hippocampus of HI rats as early as 24 hours after the lesion, while no elevation is detected in CP rats at 28 days post-lesion (data under publication). These results suggest that ER stress is triggered early in HI rats but has been resolved 28 days after the brain injury in CP rats.

The first objective is to determine whether CP rats exhibit early cerebral ER stress, using HI rats as a control, in which stress presence is already established. The dynamics of ER stress and UPR activation will be analyzed between 1- and 7-days post-lesion for the HI model, and between 1 and 21 days for the CP model. We will search for ER stress and UPR markers by RT-qPCR in different regions of the brain, as well as in muscles and blood at these specific times. This study will allow us to: (i) characterize the dynamics of ER stress onset, (ii) identify the brain regions most affected in HI and CP rats, and (iii) determine the optimal time for applying ER stress inhibitors in these two models.

The second objective is to establish proof of concept for the beneficial effect of newly identified ER stress inhibitors (currently under publication) on the motor abilities of HI and CP rats. We will compare their motor abilities to those of untreated animals, using the IMAGINE team’s expertise in movement analysis.

Scientific Environment, Positioning in the International Context

This project contributes to the international community's efforts to identify therapeutic pathways that could pharmacologically limit the motor consequences of early brain injuries in newborns. Our collaboration with the University of Geneva provides us with relevant animal models of CP that mimic the brain injuries seen in children who have suffered hypoxia, infection during pregnancy, or perinatal anoxia. Furthermore, the new ER stress inhibitors we have identified, some of which are already medications, represent a real asset for this ambitious project. It is worth noting that these ER stress inhibitors have shown effectiveness in Parkinson's disease and oculopharyngeal muscular dystrophy (patent in preparation). Some of these molecules are currently part of a maturation project led by SATT Ouest Valorisation, which will benefit this CP project.

We have recently obtained funding for the creation of a small animal movement measurement laboratory, which will be located at the animal facility of the Faculty of Medicine at UBO. The development of this laboratory will mirror the human movement laboratory at the CHU of Brest, where the movements of children with CP are measured. In addition to the absence of a small animal movement analysis laboratory in the Grand Ouest, aligning this small animal laboratory with the human movement laboratory will provide a unique opportunity to assess the effectiveness of therapies in preparation for clinical trials.

The thesis student will hold a Master 2 degree in biology or an equivalent qualification. They should possess solid theoretical and practical skills in molecular biology (RNA extraction, qPCR), biochemistry (western blot), and cell culture (BSL2). Experience in animal care (level 1) and knowledge of working in a BSL2 laboratory would be advantageous. However, it should be noted that the host team has the expertise to train a student in these techniques.

The recruited individual should be highly motivated, a good team player, and possess strong communication and adaptability skills. They should be meticulous, rigorous, and have a well-defined career plan. Part of the thesis work will be conducted at the NeuroCenter of the University of Geneva, under the supervision of Stéphane Sizonenko and Eduardo Sanches.