Job ID: 98691

Abnormalities in sensorimotor integration in mTORopathies – underlying mechanisms and potential treatments

Position: Ph.D. Student

Deadline: 31 December 2022

Employment Start Date: 1 February 2022

Contract Length: 4 years

City: Rotterdam

Country: The Netherlands

Institution: Erasmus MC

Department: Neuroscience

Description:

The candidate will study the mechanisms underlying sensorimotor integration problems in mTORopathies, aiming to identify possible treatments, as described in more detail below:

Problem: The mechanistic target of rapamycin (mTOR) pathway is a highly complex and conserved signaling cascade involved in biomass synthesis, growth and cell proliferation. Specifically, during brain development, it has been proposed that a tight regulation of mTOR signaling is required for sustaining cell cycle length and re-entry, defining pluripotency status and triggering differentiation. Therefore, mutations along this pathway frequently lead to complex monogenic neurodevelopmental disorders (also known as mTORopathies), characterized by vast and heterogeneous phenotypes that can include increased prevalence of immunodeficiencies and malignancies, as well as megalencephaly, epilepsy, intellectual disability and autism spectrum disorder. However, there are currently only a handful of treatments available that address these neurological symptoms, all with significant adverse effects.

Solution: There are currently no biomarkers that can predict the level of intellectual disability or the severity of the ASD deficits in patients with mTORopathies. Interestingly, new insights suggest that sensorimotor network deficits, which reflect underlying brain dysfunction, have a high predictive value for determining neurodevelopmental phenotypes. People with ASD, for example, often present with sensorimotor deficits, which could be easily measured and potentially used as a marker for early diagnosis. Thus, the validation and establishment of new sensorimotor tools that enable a quicker and objective identification of neuropsychiatric phenotypes is critical.

Plan: In this project, the PhD student will investigate, through in vivo approaches and cell cultures, the cascade of events in mouse models of human mTOR-pathway disorders that lead from specific mutations to sensorimotor deficits. The resulting understanding of the mechanisms underlying sensorimotor deficits will be used to then the ability of potential treatments to alleviate the deficits.

Approaches: This work will utilize electrophysiological recordings, microscopy and imaging techniques, combined with various behavioral tasks to analyses sensorimotor (in)abilities. The student will then test different intervention methods, including ultrasound-triggerable drug delivery systems developed by the consortium. The treatment methods will be tested first in organotypical slices and human iPSC cerebellar cultures before applying them to mouse models.

Profile

We are looking for a highly motivated and goal-oriented researcher with a M.Sc. degree in nanobiology, neuroscience, cell biology, biophysics, biomedical sciences, or related field. The ideal candidate has a background in molecular techniques (qPCR, Western blots etc.), behavioral techniques and electrophysiology, and is interested in learning how to use neuronal cell cultures to answer neurobiological questions in health and disease. The candidate should be fluent in English, have basic knowledge of at least one coding language (Pyton or MATLAB) and be motivated to work in an ambitious and collaborative research team.