RNA In Situ-ations: Unravelling the Molecular Basis for Myotonic Dystrophy through HighResolution Cryo-Electron Tomography of Disease State RNA Condensates


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  Prof J D Brook  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

We aim to uncover the molecular mechanisms underlying RNA misfolding diseases, particularly focusing on myotonic dystrophy (DM). In DM, both voluntary and involuntary muscles progressively degenerate in the body, affecting normal functioning of the eye, heart, endocrine system and central nervous system. DM is caused when repetitive CUG motifs in the DMPK mRNA fold abnormally and form RNA-protein condensates with the MBNL proteins in the nuclei of muscle cells. This process inhibits MBNL's regular function in mRNA splicing and results in DM symptoms.

DM has been extensively studied over the past several decades. Yet, we don’t fully understand the molecular interactions between the disease state DMPK mRNA and MBNL proteins that lead to the observed pathophysiology. To address this gap in knowledge, we will employ a multidisciplinary approach involving cell biology, various microscopy techniques, and structural biology methods to directly study native DMPK mRNA-MBNL interactions in the disease state and in the presence of small molecule inhibitors.

This research holds profound implications for millions of people facing life-altering symptoms due to RNA misfolding diseases. By shedding light on their molecular intricacies, the project will contribute to collaborative publications of global significance, novel drug development, clinical applications, and intellectual property advancements.

Biological Sciences (4)

Funding Notes

This is a fully funded studentship provided by the Medical Research Council. If successful, you will receive a stipend (currently £18,622 per year for 2023/24) and tuition fee waiver for 4 years. Successful candidates will also receive an allowance for a laptop, a travel and conference allowance plus allowance for laboratory/PhD running costs.
Click on the institution website link which will redirect you to the MRC AIM website which contains full application information including application forms to complete. Please ensure you submit your application before the deadline of midday (GMT) Friday 12 January 2024 as late applications will not be considered.

References

Brook, J D, et al. (1992) Molecular basis of Myotonic Dystrophy: Expansion of a Trinucleotide (CTG) Repeat at the 3' end of a transcript encoding a protein kinase family member. Cell, 68, 799-808.

Ketley A, et al. and Brook JD. (2014). High-content screening identifies small molecules that remove nuclear foci, affect MBNL distribution and CELF1 protein levels via a PKC-independent pathway in myotonic dystrophy cell lines. Human Molecular Genetics. 23(6), 1551-62.
Ketley A, et al. and Brook JD (2020). CDK12 inhibition reduces abnormalities in cells from patients with myotonic dystrophy and in a mouse model. Science Translational Medicine, 12 (541): eaaz2415.
Christel Depienne and Jean-Louis Mandel (2021) 30 years of repeat expansion disorders: What have we learned and what are the remaining challenges. The American Journal of Human Genetics 108, 764–785.

Where will I study?