Characterisation of how pro-peptide regions of collagen control extracellular matrix homeostasis, in health and musculoskeletal diseases
About the Project
Collagen-I (‘collagen’ from hereon) is the most abundant protein in the human body (circa 25% of total protein mass), providing structure to organs with very different functions (e.g. tendons vs lungs). Collagen deposition is a tightly controlled process; dysregulation underpins many pathologies and age-related conditions, including fibrosis, heart disease, and poor wound-healing. Genetic mutations in collagen leads to connective tissue disorders such as osteogenesis imperfecta and Ehlers Danlos syndrome. Despite collagen’s fundamental importance, therapeutics for diseases associated with collagen have been lacking, due to conceptual hurdles in understanding how collagen is assembled/removed. Closing these knowledge gaps forms the basis of this project.
Previously we have found that 1) collagen homeostasis is controlled by the circadian rhythm), 2) protomeric collagen secretion is separately controlled to fibrillogenesis, and 3) enhanced endosomal recycling may drive fibrotic progression. Preliminary data in the lab also indicates a previously uncharacterised function for the propeptide region in regulating collagen-I homeostasis.
Using a combination of CRISPR-Cas9 genome editing (e.g. endogenous protein tagging), protein structural analyses (e.g. crystallography), protein biochemistry (e.g. nanobody screening), in vitro 2D/3D cell culture systems and in vivo mouse models, this PhD project aims to characterise the propeptide region of collagen-I, and further interrogate the molecular mechanisms to how collagen-I homeostasis is regulated.
Training/techniques to be provided
This project will utilise the following techniques (not exhaustive): Mouse models, CRISPR gene knockout/knockin, confocal microscopy, flow cytometry, electron microscopy (EM), protein expression and structure (crystallography, cryo-EM), protein biochemistry, cell culture, primary cell culture, mass spectrometry analyses, biomechanics analyses.
The student will be trained both in terms of scientific techniques and analytical analyses. They will also have extensive training in scientific writing, poster presentation and oral presentation skills. Students will have access to online training courses and will have ample opportunities to present at internal and external meetings and conferences.
Entry Requirements
Applicants 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 a relevant subject area.
How to Apply
For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select the PhD Cell Matrix Biology & Regenerative Medicine.
For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit https://www.bmh.manchester.ac.uk/study/research/international/
Equality, Diversity & Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website
https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/
Funding Notes
Details of our different fee bands can be found on our website View Website
References
2) Pickard A, Calverley BC, Chang J, Garva R, Lu Y, Kadler KE. Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells. PLOS Pathogens, 2021; 17(9), 31009840.
3) Zacharchenko T, Kalverda A, Wright SC. Structural basis of Apt48 inhibition of BCL6 BTB-domain. Structure, 2022 Mar 3;396-407.
4) Godwin ARF, Dajani R, Zhang X, Thomson J, Holmes DF, Adamo CS, Sengle G, Sherratt MJ, Roseman AM, Baldock C. Fibrillin microfibril structure identified long-range effects of inherited pathogenic mutations affecting a key regulatory latent TGFb-binding site. Nature Structure. 2023 30:608-618.
5) Lockhart-Cairns MP, Cain SA, Dajani R, Steer R, Thomson J, Alanazi YF, Kielty CM, Baldock C. Latent TGFβ complexes are transglutaminase cross-linked to fibrillin to facilitate TGFβ activation. Matrix Biol. 2022 107:24-39.
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