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Investigating the role of tRNA fragments in ALS models S&T27

  • School: School of Science and Technology
  • Study mode(s): Full-time / Part-time
  • Starting: 2022
  • Funding: UK student / EU student (non-UK) / International student (non-EU) / Fully-funded

Overview

NTU's Fully-funded PhD Studentship Scheme 2022

Project ID: S&T27

Amyotrophic Lateral Sclerosis (ALS) is a progressive degenerative disease with no known cure and limited treatment options. Pathological aggregates containing TDP-43 protein are present in 97% ALS cases suggesting TDP-43 plays a key role in the disease process. Mutations in the ribonuclease Angiogenin have been identified in patients with ALS, indicating its function is crucial for motor neuron survival. Angiogenin is upregulated under stress conditions where it cleaves transfer RNAs to generate tRNA fragments. tRNA fragments are a novel class of non-coding RNA, similar to microRNAs, which have been found to be elevated in patients with a slow progressing form of ALS. In this project we aim to investigate the biogenesis and function of tRNA fragments in cellular and Drosophila models of ALS.

For in vitro ALS models we will use induced pluripotent stem cells (iPSCs) from ALS patients harbouring mutations in the TARDBP gene which encodes TDP-43 protein, and healthy controls. iPSCs will be differentiated into motor neurons in the lab to analyse tRNA fragments and investigate factors that influence tRNA fragment biogenesis. Using a range of molecular biology techniques, we will investigate the role of tRNA fragments in protein translation, stress granule formation, and pathways that are regulated in response to physiological stress conditions. We will analyse survival following transient and prolonged exposure to stress and determine whether manipulating tRNA fragment levels can influence motor neuron survival.

In a complementary in vivo approach, we will use Drosophila melanogaster (fruitfly) models genetically engineered to overexpress mutant TDP-43 protein in motor neurons and the eye. Here we will investigate whether manipulating levels of tRNA fragments can influence TDP-43 pathology, locomotion defects and survival in fly models of ALS. Together these two approaches will provide a comprehensive understanding of tRNA fragment biogenesis and function in motor neuron disease.

The successful applicant will gain experience in a wide range of techniques including cellular and molecular biology, biochemistry, RNA and protein analysis techniques, immunocytochemistry and image analysis, and Drosophila melanogaster biology and genetic manipulation techniques. The student will join a vibrant neurodegenerative research environment at NTU with expertise in a range of different models and scientific approaches.

The supervisory team consist of Director of Studies Dr Marion Hogg and co-supervisor Dr Shreyasi Chatterjee.

School strategic research priority

This project aligns with the CHAUD Research Centre & the Aging theme and complements the established portfolio of neurodegenerative disease research at NTU.

Entry qualifications

For the eligibility criteria, visit our studentship application page.

How to apply

For guidance and to make an application, please visit our studentship application page. The application deadline is Friday 14 January 2022.

Fees and funding

This is part of NTU's 2022 fully-funded PhD Studentship Scheme.

Guidance and support

Download our full applicant guidance notes for more information.

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