PhD Studentship: Investigating the interaction of APOE4 with TDP43 proteinopathy in driving neurodegeneration

PhD Studentship:

Investigating the interaction of APOE4 with TDP43 proteinopathy in driving neurodegeneration

Project Description

The University of Exeter’s Living Systems Institute is inviting applications for a PhD studentship fully-funded by BRACE to commence on 25th September 2023 or as soon as possible thereafter. 

TDP43 or (TARDBP) is an RNA-binding protein with critical functions in neurons, including alternative splicing and microRNA biogenesis. In many neurodegenerative diseases associated with dementia such as Frontotemporal dementia (FTD), limbic associated TDP43 encephalopathy (LATE) and Alzheimer’s disease (AD), TDP43 mislocalizes to the cytoplasm and frequently aggregates into inclusions that can lead to neurodegeneration. However, the downstream effects of TDP43 mislocalization on neurons are incompletely understood. Genetic variants in certain genes are associated with increased risk of neurodegenerative disease. For example, the APOE4 allele is associated with increased risk of late-onset AD and LATE. However, whether these genetic variants act synergistically or independently of TDP43 mislocalization is largely unknown. In this project, the student will investigate the effect of the APOE4 allele on human iPSC-derived neurons in the presence or absence of TDP43 pathology and deploy a combination of imaging-based cellular assays and genomic tools to understand the mechanisms driving neuronal dysfunction.

The proposed study will not only develop a fully characterized new model to study TDP43 proteinopathies but will also highlight how genetic risk synergizes with a key biochemical hallmark to drive neuronal dysfunction in dementia. Additionally, the genomic studies highlighted will discover new candidates for therapeutic intervention.

The student will be based in the LSI, an interdisciplinary initiative between Engineering, Mathematics, Physics, Biosciences and the Medical School. The LSI houses a high-content high-throughput imaging platform that can conduct phenotypic screens on neurons. We also have access to an imaging suite that includes confocal and super-resolution microscopes, and plate readers for combined fluorescence/luciferase assays for neuronal viability read-outs enabling the student to receive training in state-of-the-art equipment for phenotypic assays. They will be a part of a growing LSI early career researcher network (ECRN) comprised of over 100 PhD students and post-doctoral fellows. The student will also be embedded within the Complex Disease Epigenetics Group at the Medical School. They will join a dynamic group with a vibrant environment for early career researchers at the Wellcome Wolfson Centre for Medical Research based in the new RILD building equipped with cutting edge facilities for genomics research. The student will receive training in stem-cell biology, state-of-the-art imaging for phenotypic assays as well as genomics and bioinformatics. They will interact with researchers across mathematics, physics and computational neurobiology gaining a wide experience in different but relevant disciplines that will help frame future postdoctoral grants and fellowships.

This award provides annual funding to cover Home tuition fees and a tax-free stipend.

For students who pay Home tuition fees the award will cover the tuition fees in full, plus at least £18,622 per year tax-free stipend. 

Entry requirements

Applicants for this studentship must have obtained, or be about to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science or technology. 

If English is not your first language you will need to meet the required level as per our guidance at https://www.exeter.ac.uk/pg-research/apply/english/

The closing date for applications is midnight on Sunday 15^th October 2023.

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