PhD: Microglial drug targets for rapid translation in MND

PhD Studentship: Revolutionizing ALS Drug Discovery through Human Microglia at The University of Sheffield

“Identifying and Validating Druggable Microglial Targets in Amyotrophic Lateral Sclerosis Using Patient-Derived Models and Single-Cell Multiomic Data”

Host Institution: University of Sheffield

Primary Supervisor: Dr Richard Mead

Secondary Supervisors: Professor Jonathan Cooper-Knock & Dr. Matthew Livesey

The Opportunity

Are you passionate about neuroscience and eager to contribute to the hunt for a cure for Amyotrophic Lateral Sclerosis (ALS/MND)?

This PhD project offers a unique opportunity to bridge the gap between clinical genetics, stem cell biology, and drug discovery. You will join a world-leading team at the University of Sheffield to tackle a critical bottleneck in ALS research: the lack of effective therapies targeting neuroinflammation.

By moving away from non-predictive animal models and utilizing cutting-edge human iPSC-derived models, you will help identify and validate the next generation of therapeutic targets.

The Scientific Challenge

Microglial dysfunction and chronic neuroinflammation are key drivers of ALS progression. However, clinical trials targeting these pathways have historically failed, largely due to a lack of understanding of human microglial biology.

This project aims to change that.

By integrating functional lab assays with massive transcriptomic and genetic datasets, you will prioritize “druggable” targets that have real translational potential for human patients.

What You Will Do

This is a multidisciplinary project designed to provide comprehensive training in modern translational neuroscience. Your research will focus on three core pillars:

• Advanced Cell Culture: You will establish and characterize patient-derived iPSC microglia carrying C9orf72 and TDP-43 mutations (alongside isogenic controls). You will also utilize co-culture systems with patient-derived iNeurons to assess neurotoxicity.

• Big Data & Multiomics: You will mine a massive in-house single-nucleus RNA and ATAC sequencing dataset (sourced from >500,000 nuclei from ALS motor cortex) and cross-reference this with Project MinE genetic data to find disease-specific signatures.

• Drug Discovery & Validation: You will use public databases (Open Targets, UniProt) to assess the “druggability” of your findings and validate the top-ranked targets using small molecules in your human cell models.

Why Choose This Project?

• World-Class Supervision: Benefit from the combined expertise of Dr Richard Mead (Drug Discovery/Translational Neuroscience), Prof. Jonathan Cooper-Knock (Multi-omics /Clinical Neurology), and Dr. Matthew Livesey (Neurophysiology/Stem Cell Biology).

• Cutting-Edge Techniques: Master highly sought-after skills, including iPSC differentiation, electrophysiology, disease models, drug discovery and bioinformatics.

• Impact: This is not just basic research; it is a translational pipeline. Your work will directly contribute to the development of novel therapeutic strategies for a devastating terminal illness.

• Collaboration: The project includes collaboration with Cardiff University (Dr Owen Peters) to ensure access to robust differentiation protocols and expertise.

Ideal Candidate Profile

We are looking for a highly motivated candidate with a background in neuroscience, cell biology, genetics, or a related field. An interest and ideally some experience in stem cell models, neuroinflammation, and data analysis is highly desirable.