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Precision Medicine DTP - Deciphering the mechanism that masks an endothelial formylated peptide receptor


College of Medicine and Veterinary Medicine

About the Project

Background

Endothelial cells (ECs), the building blocks of blood vessels form a tight barrier between the blood and the surrounding tissue. During inflammation, barrier permeability is temporarily increased, allowing some leakage of protein-rich plasma. Excessive vascular leakage can have disastrous consequences. This is exemplified by acute respiratory distress syndrome (ARDS), a life-threatening complication of serious pre-existing conditions (e.g. COVID-induced pneumonia) and a leading cause of deaths in critical care units. In ARDS increased
permeability of the capillary-alveolar barrier and excessive leukocyte infiltration promote leakage of plasma fluid into the alveolar space, compromising respiratory function. Due to the lack of treatment options, current therapies rely on supportive care, e.g. mechanical
ventilation. Unlike mammalian proteins, mitochondrial and bacterial proteins are formylated. Formylated peptides are pathogen/danger associated molecular patterns (DAMPs/PAMPs) that potently activate formylated peptide receptor (FPR)-expressing leukocytes. We recently made the surprising observation that ECs also express FPR1 and that endothelial FPR1 is normally ‘masked’. ECs in which FPR1 is ‘unmasked’ are characterized by increased cell surface FPR1 and hyper-responsiveness to formylated peptide (manuscript in preparation). Interestingly, unmasking FPR1 in mouse models had particularly strong effects on endothelial permeability in
the lung, suggesting that this mechanism could be important in ARDS. The present project will use state-of-the-art technology to identify the molecular mechanism that regulates (un)masking of endothelial FPR1 with a view to identifying whether/how this
process may be amenable to pharmacological intervention.

Aims

To decipher the molecular mechanism that underpins ‘masking’ of endothelial FPR1, a genomewide CRISPR knock-out screen will be performed. Using a combination of experimental work (Vermeren) and bioinformatic analyses (Chandra, Kutter), you will identify and validate genes that are involved in the regulation of endothelial FPR1 by
- Optimizing lentiviral transduction of ECs with a genome-wide CRISPR library
- Employing FACS sorting of ECs to enrich potential hits (characterized by increased /
decreased cell surface FPR1)
- Performing next generation sequencing (NGS) of the enriched population, identifying
genes that were knocked out in these cells using bioinformatics
- Using bioinformatics to separate true hits from false positives; if required perform a
secondary screen to improve faithfulness.
- Validating hits experimentally.

Training outcomes

This project would suit a student with a life science background and a keen interest in bioinformatics or vice versa. The student will be fully trained in wet and dry science to cover all the experimental approaches and powerful bioinformatics tools required for to unravel this
complex regulatory process.

This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with University of Glasgow.

http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note, you must apply to one of the projects and you must contact the primary supervisor prior to making your application. Additional information on the application process is available from the link above.

For more information about Precision Medicine visit:
http://www.ed.ac.uk/usher/precision-medicine

Funding Notes

Start: September 2021

Qualifications criteria: Applicants applying for an MRC DTP in Precision Medicine studentship must have obtained, or will soon obtain, a first or upper-second class UK honours degree or equivalent non-UK qualification, in an appropriate science/technology area. The MRC DTP in Precision Medicine grant provides tuition fees and stipend of at least £15,285 (UKRI rate 2020/21).

Full eligibility details are available: View Website

Enquiries regarding programme:

References

Acosta & Sieger (2020) Pathogenesis of COVID-19-induced ARDS. Eur Respir J in press DOI:10.1183/13993003.02049-2020

Zhang et al (2010) Circulating mitochondrial DAMPs cause inflammatory responses in the lung. Nature 464, 104.

Sanson et al (2018) Optimized libraries for CRISPR-Cas9 genetic screens with multiplemodelities. Nat Commun 9, 5416.

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