Job ID: 118122
PhD project: Human iPSC-based modeling platforms to study the consequences of astrocytic reactivity in Alzheimer’s disease: from molecular investigations to candidate validation
Position: Ph.D. Student
Deadline: 14 April 2024
Employment Start Date: 1 October 2024
Contract Length: 3 years
City: Marseille
Country: France
Institution: Aix-Marseille Université
Department: INP
Description:
The NeuroSchool PhD Program of Aix-Marseille University (France) has launched its annual calls for PhD contracts for students with a master’s degree in a non-French university. This project is one of the 13 proposed projects. Not all proposed projects will be funded, check our website for details.
State of art: Synapse loss and reactive gliosis are amongst the best correlates of early memory deficits in Alzheimer’s disease (AD) patients. Abeta and Tau pathology affects neurons, but also induce cell non-autonomous responses in astrocytes that are increasingly recognized as drivers of the disease. Several studies revealed that modulation of astrocyte reactivity can alleviate AD symptoms in mouse models and also prevent from astrocytic changes related to neuronal support, suggesting a critical role for both astrocytes and inflammation in AD initiation/progression. Therefore, research on AD should move beyond the neuronal focus and include astrocyte-based disease mechanisms at the earliest stages of the disease. This prompts the need to study whether and how some specific molecular changes related to astrocyte reactivity could lead to alterations impacting the neuron-astrocyte crosstalk and ultimately leading to AD pathology. This could pave the way for therapeutic applications targeting the astrocytes.
Objectives: The overall objective is to demonstrate that astrocytes are at the core of molecular underpinnings in AD, specifically through pathogenic feedback loops in which astrocytic reactivity may be involved in early neuronal deficits in AD. The first task will be to determine the cellular and functional consequences of modulations targeting a selection of astrocytic proteins involved in astrogliosis and possibly at play in AD. In a second task, we will determine the consequences of those astrocytic manipulations on AD pathological marks in human neurons.
Methods: The project will involve the use of human iPSC-derived astrocyte cultures, neuron-astrocytes co-cultures (e.g. microfluidic-based), as well as cerebral organoids enriched for astrocytes. From those models, we will use genetic manipulations in astrocytes specifically (e.g. using CRISPR-Cas9 based strategies) and perform a battery of evaluations on both astrocytes and neurons including for instance transcriptomic (e.g. RNAseq) and proteomic analyses, immunostainings combined with imaging (e.g. synaptic markers), as well as functional assays (e.g. ca2+ imaging, MEAs, axonal transport using live-cell imaging).
Expected results: We expect to identify at least one candidate protein that is involved in astrocyte reactivity and from which its experimental modulation in human astrocytes is able to reduce or delay AD-related pathological marks in human neurons.
Feasibility: Our team has strong expertise with hiPSC-based disease modeling and the proposed models are already implemented. We also have experience with CRISPR-Cas9 based genetic manipulation in hiPSCs. We will also take advantage of our previous work that led to the identification of TAGLN3 as a new candidate of interest that will be included in this project, along with other candidate proteins. Moreover, we have the necessary expertise and equipment to perform the different analyses included in the project either in our lab or through a network of collaborators. Last, the running costs for this project are already secured.
Expected candidate profile: The candidate is expected to have a solid background in the field of Neuroscience and a strong interest for neurodegenerative diseases. First-hand experience with cell culture (hiPSC) and genetic modifications (CRISPR) would be a strong plus. Among the many soft skills we are expecting from the candidate, the most important will be Teamwork, Analytical and critical thinking, Autonomy, Flexibility and adaptability, Communicative, Co-operation.