About the Project
Endothelial cell proliferation and lymphatic cell proliferation known as angiogenesis and lymphangiogenesis respectively are both regulated by ligands in the VEGF signalling pathway. In general endothelial and lymphatic cells in healthy individuals are quiescent and do not proliferate. Proliferation of these cells occurs in the adult only under specific conditions such as in response to wounding, in response to inflammation, or in response to pathogens. Although much is known about how the endothelial and lymphatic cells are induced to divide relatively little is known about the proteins that maintain the non-proliferative state. Previous Studies have shown that the PRH protein regulates endothelial growth as well as haematopoietic growth and lymphatic development (Stepanova et al 2016; Noy et al 2010; Gauvrit et al 2018). Recent work has revealed the identity of transcription factor complexes that work with PRH to restrain cell division. We are interested in understanding the molecular mechanism whereby signalling from the external environment impacts on the activity of the transcription factor complexes to overcome quiescence. Recent studies have shown that many transcription factors form molecular condensates in cells by a process known as liquid-liquid phase separation and that the formation of these condensates is important in transcription factor function (reviewed by Boija et al., Cancer Cell 2020). In this project we will investigate the formation of transcription factor complexes with other proteins and also the formation of transcription factor condensates in vitro and in living cells using a variety of technologies including high-resolution cell imaging, quantitative fluorescence microscopy, spectroscopies and biophysical techniques, chromatin immunoprecipitation sequencing, site-directed mutagenesis and mass spectrometry. We will also develop mouse models to understand the role of PRH and partner proteins in endothelial quiescence. These multidisciplinary studies will give us a better understanding of how transcription factors function in endothelial and lymphatic cells and we hope that this will reveal new potential targets for therapeutic interventions.
This project is a collaboration between the Jayaraman, Gaston and Benest laboratories at the University of Nottingham UK.
To be considered for this studentship, please apply online at: https://www.nottingham.ac.uk/pgstudy/course/research/Medicine-PhD
Please include in your application:
- A detailed CV;
- Names and addresses of three referees;
- A covering letter highlighting your research experience/capabilities;
- At the top of your letter please put the name of your proposed supervisor and the title of the research
Funding Notes
We will consider applications from self-funded prospective students with:
- a good biomedical or related degree, with interests in any of the areas outlined above,
- a good command of the English language (written and spoken) as outlined in the postgraduate prospectus,
competence with computers and data handling,
- a source of funding to cover tuition fees and bench fees (note that tuition fees are different for Home and EU students than for International students). More information regarding fees can be found under the ‘Medicine’ heading at:
View Website
References
Green KR, Beazley Long N, Lynch AP, Allen CL, Benest AV (2022). Quantification of pathological angiogenesis using laser induced choroidal neovascularisation. Methods Mol Biol, 2441:223-231
Tabrizi ZB, Green KR, Lynch AP, Ahmed NS, Beazley-Long N, Benest AV (2022). Simple Gene Knockdown in Endothelial Cells Using Short Interfering RNA Oligonucleotides. Methods Mol Biol;2441:251-255
Horder JL, Pinel GD, Mongan NP, Benest AV (2022). Identification of novel candidate lymphangiogenesis regulators by unsupervised clustering of RNASeq data. 2441:369-426
Tabrizi Z, Ahmed NS, Horder JL, Storr SJ, Benest AV. (2021) Transcription factor control of lymphatic quiescence and maturation of lymphatic neovessels in development and physiology. Frontiers in Physiology (12): 672987
Gauvrit S, Villasenor A, et al., (2018) The homeobox transcription factor PRH/HHEX is an upstream regulator of the VEGFC/VEGFR3 /PROX1 signaling axis. Nature communications (2018) Jul 13;9(1):2704.
Stepanova V$, Jayaraman PS$, et al ,. (2016) Urokinase-type plasminogen activator (uPA) promotes angiogenesis by attenuating Proline-rich homeodomain protein (PRH) transcription factor activity and de-repressing vascular endothelial growth factor (VEGF) receptor expression. Journal Biological Chemistry Jul 15;291(29):15029-45.
Noy P, Williams H, Sawasdichai A, Gaston K, Jayaraman PS (2010) PRH/Hhex controls cell survival through coordinate transcriptional regulation of vascular endothelial growth factor signaling. Molecular Cellular Biology 30(9):2120-34
Soufi, A., Sawasdichai, A., Dafforn, T., Smith, C., Jayaraman, P.S., and Gaston, K. (2010) DNA compaction by the higher-order assembly of Proline-Rich Homeodomain protein oligomers. Nucleic Acids Research, 38:7513-7525.
Williams, H., Jayaraman, P.S., and Gaston K. (2008) DNA wrapping and distortion by an oligomeric homeodomain protein. Journal of Molecular Biology, 383: 10-23.
Boija,A., Klein, I.A., and Young R.A. (2020) Biomolecular condensates and cancer. Cancer Cell 39 [doi.org/10.1016/j.ccell.2020.12.003].
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